The most common side effects of azathioprine are nausea, vomiting, and diarrhea, followed by a drop in white blood cell counts that leaves you more vulnerable to infections. Most people tolerate the drug well enough to stay on it long term, but because azathioprine suppresses the immune system and affects how your body produces blood cells, it requires regular blood monitoring, especially in the first two months of treatment.
Digestive Problems
Stomach-related side effects are the ones you’re most likely to notice first. Nausea is the most frequently reported complaint, often accompanied by vomiting, diarrhea, or a general sense of indigestion. Some people also experience abdominal pain. These symptoms tend to be worst in the early weeks of treatment and often improve as your body adjusts. Taking the medication with food or splitting the dose across the day can help reduce nausea for many people.
A smaller but meaningful number of people develop drug-induced pancreatitis, an inflammation of the pancreas that causes intense upper abdominal pain, sometimes with nausea and vomiting. Across studies of patients with Crohn’s disease, the risk of pancreatitis with azathioprine is about 3.8%, compared to roughly 0.2% with a placebo. It typically shows up around three to four weeks after starting the medication. The good news is that azathioprine-induced pancreatitis is usually mild and resolves once the drug is stopped, but it does mean you shouldn’t try azathioprine again.
Low Blood Cell Counts
Azathioprine works by dialing down your immune system, and it does this partly by slowing the production of white blood cells in your bone marrow. Sometimes it dials things down too far, a condition called myelosuppression. This can show up as a dangerously low white blood cell count, low platelet count, or both. You won’t necessarily feel this happening, which is why blood tests are essential.
The highest risk period is the first eight weeks of therapy. In a large study of nearly 2,000 new users, severe drops in white blood cells occurred most often during this window, with a median time of about 13 to 14 days from a normal count to a severely low one. After the first two months the risk drops substantially, though late-onset cases can still occur months or even years into treatment. Signs to watch for include unexplained fevers, persistent sore throats, unusual bruising, or bleeding that’s hard to stop.
Liver Enzyme Elevations
Between 5% and 15% of people on azathioprine develop mild, temporary elevations in liver enzymes. In most cases this causes no symptoms at all and only shows up on blood work. These elevations often resolve on their own or after a dose adjustment.
Less commonly, azathioprine can cause more significant liver injury. This can take several forms, from a pattern that looks like hepatitis (inflammation of liver cells) to one that resembles a blockage in bile flow. Symptoms of meaningful liver problems include yellowing of the skin or eyes, dark urine, persistent fatigue, or pain in the upper right side of your abdomen. Routine blood tests are designed to catch liver changes early, well before symptoms develop.
Infections
Because azathioprine suppresses immune function, you become more susceptible to infections while taking it. Common colds and upper respiratory infections may hit harder or last longer. More serious infections, including certain viral and fungal infections that a healthy immune system would normally keep in check, can occasionally occur. Staying current on vaccinations before starting azathioprine is important, since some live vaccines aren’t safe to receive while on the drug.
Long-Term Cancer Risk
Long-term use of azathioprine is associated with a higher risk of certain cancers, particularly skin cancer and lymphoma. The skin cancer risk is driven by the same immune suppression that makes the drug effective. The connection is strongest for squamous cell carcinoma, a type of non-melanoma skin cancer. Organ transplant recipients on immunosuppressive regimens that include azathioprine face up to a hundredfold increase in skin cancer risk compared to the general population, though the risk is lower for people taking azathioprine alone for autoimmune conditions. Using sunscreen, wearing protective clothing, and getting annual skin checks are practical ways to manage this risk.
A meta-analysis published through the Mayo Clinic found that current azathioprine users had roughly a fivefold higher risk of lymphoma compared to the general population. The absolute risk was highest in patients over 50, at about 1 case per 354 patient-years of treatment. To put that in perspective, that’s still a small absolute number, but it’s meaningfully higher than baseline. Former users who had stopped the drug did not appear to carry the same increased risk, suggesting the effect is tied to active use.
Why Genetics Matter
Your body breaks down azathioprine using specific enzymes, and some people are genetically wired to process the drug much more slowly than others. Two enzymes in particular, known as TPMT and NUDT15, play a major role. About 1 in 300 people have very low activity of TPMT, and these individuals are at serious risk of severe bone marrow suppression even at standard doses.
Many doctors now order a genetic test or an enzyme activity test before prescribing azathioprine. If you’re found to be an intermediate metabolizer, you’ll typically start at 30% to 80% of the usual dose. If you’re a poor metabolizer, your doctor will likely recommend an alternative medication entirely, at least for non-cancer conditions. This testing has made azathioprine significantly safer by identifying high-risk individuals before they ever take their first dose.
What Blood Monitoring Looks Like
Before starting azathioprine, you’ll have blood tests checking your liver function, kidney function, and blood cell counts. For the first eight weeks, expect blood draws at least once a week. This frequent monitoring aligns with the window of highest risk for bone marrow suppression. After that initial period, testing becomes less frequent, often stretching to every few months once your counts have been stable. If your dose changes or you start a new medication that could interact with azathioprine, your doctor may temporarily return to more frequent testing.
Azathioprine During Pregnancy
Azathioprine is one of the few immunosuppressive drugs considered relatively safe during pregnancy. Current evidence reviewed by the American College of Obstetricians and Gynecologists does not show that azathioprine causes birth defects. Some studies have noted a possible link to preterm birth and lower birth weight, but for many women with autoimmune conditions or organ transplants, the risk of stopping the drug and experiencing a disease flare is considered greater than the risk of continuing it. The older practice of routinely stopping azathioprine around 32 weeks of pregnancy is no longer supported by current data.