Prospective follow-up for a median of 35 months of a French cohort of 19 486 patients with inflammatory bowel disease showed a nearly 4-fold increase in the risk of lymphoma in patients exposed to azathioprine or mercaptopurine (relative risk 3.75; 95% confidence interval 1.59 to 8.85). This risk should be taken into account when weighing the likely benefits of these drugs in treatment of patients with severe chronic inflammatory bowel disease no longer responding to first-line treatment.