Non-Hodgkin lymphoma (NHL) has no single cause. It develops when white blood cells called lymphocytes acquire genetic errors that make them grow out of control, but what triggers those errors varies widely. An estimated 79,320 new cases will be diagnosed in the United States in 2026 alone, and the median age at diagnosis is 68. The disease is about 40% more common in men than women, with incidence rates of 22.4 per 100,000 males compared to 15.6 per 100,000 females.
Researchers have identified a web of contributing factors, from infections and immune system problems to chemical exposures and body weight. In many cases, several of these factors overlap. Here’s what’s known about each one.
Genetic Errors That Drive Lymphoma Growth
Nearly all NHL cases involve a specific type of genetic accident called a chromosomal translocation. This happens when a piece of one chromosome breaks off and attaches to another, landing a growth-promoting gene next to a stretch of DNA that’s normally very active in immune cells. The result is a gene that gets switched on far more than it should be, pushing cells to multiply or resist normal death signals.
Different translocations are linked to different subtypes. In follicular lymphoma, the most common slow-growing form, a gene that prevents cell death gets permanently activated. In mantle cell lymphoma, a gene controlling cell division is switched on in about 70% of cases. Burkitt lymphoma involves a powerful growth gene called MYC that gets hijacked by immune cell DNA. And in anaplastic large cell lymphoma, two genes fuse together to create an abnormal protein that drives uncontrolled growth.
These genetic changes aren’t inherited from your parents in most cases. They’re acquired during your lifetime, often when immune cells are rapidly dividing and rearranging their own DNA to fight infections. That normal process of DNA shuffling occasionally goes wrong, placing a cancer-promoting gene where it doesn’t belong. Recent genomic studies have further refined this picture, identifying five to seven distinct genetic subgroups within diffuse large B-cell lymphoma alone, the most common aggressive subtype.
Infections That Raise the Risk
Several viruses and bacteria are directly linked to NHL, though infection alone is rarely enough to cause it. The connection usually involves chronic stimulation or suppression of the immune system over years.
Epstein-Barr virus (EBV), which causes mononucleosis, is an important risk factor for Burkitt lymphoma, particularly in parts of Africa. In the U.S. and other developed countries, EBV is more closely tied to lymphomas in people also living with HIV. A related virus, human herpes virus 8, can infect lymphocytes and lead to a rare form called primary effusion lymphoma, again mostly in people with HIV.
HIV itself is a significant risk factor for several NHL subtypes, including primary central nervous system lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma. The virus doesn’t directly cause lymphoma but severely weakens the immune surveillance that would normally catch and eliminate abnormal cells. Human T-cell lymphotropic virus (HTLV-1), spread through bodily fluids, increases the risk of certain T-cell lymphomas.
Hepatitis C, through long-term infection, raises the risk of splenic marginal zone lymphoma. And the connection extends beyond viruses. The stomach bacterium Helicobacter pylori, known for causing ulcers, is linked to MALT lymphoma of the stomach. A healthy stomach contains no organized immune tissue, but chronic H. pylori infection causes lymphoid follicles to develop in the stomach lining. Over time, the bacteria’s constant presence stimulates immune cells to keep dividing, and that sustained stimulation can eventually tip into lymphoma. Other bacteria follow a similar pattern: Chlamydophila psittaci has been linked to MALT lymphoma around the eye, and Campylobacter jejuni to a form of intestinal MALT lymphoma seen primarily in young adults in eastern Mediterranean countries.
Immune System Problems
A weakened or overactive immune system is one of the strongest risk factors for NHL. People who take immunosuppressive drugs after organ transplantation face elevated risk because their immune system can no longer efficiently patrol for abnormal cells. But the connection goes well beyond transplant recipients.
A large cohort study found that people with any autoimmune disease had an overall 1.6 times higher risk of developing NHL compared to the general population. Some conditions carried dramatically higher risk. Autoimmune hemolytic anemia, a rare condition where the immune system destroys red blood cells, was associated with a 27-fold increase. Sjögren syndrome, which attacks moisture-producing glands, carried a nearly 5-fold increase. Celiac disease and systemic lupus erythematosus each showed roughly 4 to 5 times the risk. Even more common conditions like rheumatoid arthritis doubled the risk, and psoriasis and Hashimoto’s thyroiditis raised it by about 40%.
The mechanism likely involves two overlapping problems. First, the chronic inflammation from autoimmune disease forces immune cells to divide more frequently, increasing the chance of genetic errors. Second, many of the medications used to treat autoimmune conditions suppress immune function, reducing the body’s ability to eliminate those damaged cells.
Chemical and Occupational Exposures
Certain chemical exposures, particularly in agricultural and industrial settings, increase the likelihood of developing NHL. A large meta-analysis pooling data from 51 studies found that occupational exposure to pesticides, benzene, and trichloroethylene was associated with a 27% overall increase in NHL risk.
Benzene, a solvent found in gasoline, industrial chemicals, and some manufacturing environments, has been linked to several NHL subtypes including diffuse large B-cell lymphoma and cutaneous T-cell lymphoma. Among pesticides, lindane is the only one classified as definitively carcinogenic for NHL by the International Agency for Research on Cancer. Glyphosate-based herbicides, the active ingredient in widely used weed killers, have also been associated with increased NHL risk, though the evidence is less consistent across subtypes. The majority of studies showing significantly elevated risk (14 out of 20) evaluated people working in agriculture or with direct occupational pesticide exposure, suggesting that dose and duration of contact matter considerably.
Body Weight and Physical Activity
Obesity increases NHL risk, with stronger effects observed in men. A population-based study found that men with a BMI of 30 or higher had a 59% increased risk of NHL compared to men at a healthy weight. For women, the increase was 36%. High calorie intake showed a similar pattern: men in the highest quarter of calorie consumption had nearly double the risk, while the effect in women was smaller and not statistically significant.
The relationship also varies by subtype. Obesity-related risk was most pronounced for diffuse and other aggressive types, while excess calorie intake showed a stronger effect on follicular and small lymphocytic types. Physical activity, on the other hand, appeared protective across all subtypes, with the largest benefit seen for follicular and small lymphocytic lymphoma. The biological explanation likely involves the chronic, low-grade inflammation that accompanies excess body fat, along with hormonal changes and elevated levels of growth-signaling molecules that can promote cell division.
Why Most Cases Have No Clear Cause
Despite this long list of risk factors, most people diagnosed with NHL have no obvious exposure or condition to point to. The disease most likely arises from a combination of small genetic vulnerabilities, environmental exposures accumulated over decades, and the natural decline in immune surveillance that comes with aging. The fact that the median diagnosis age is 68 supports the idea that time itself is a factor, allowing rare genetic errors to accumulate and immune defenses to weaken. Having one or even several risk factors doesn’t make NHL inevitable, and many people with significant exposures never develop it.