Incident cases of lymphoma and leukemia in a cohort of 3824 rheumatoid arthritis (RA) patients from the Arthritis, Rheumatism and Aging Medical Information System (ARAMIS) database were identified, and the use of azathioprine, cyclophosphamide, and methotrexate was compared in a matched case-control study. Controls were matched on age, sex, year of study entry, disease duration, center, and years of follow-up. Twenty-four cases of lymphoma and 10 cases of leukemia were identified: 21% of patients with cancer versus 9% of controls had taken azathioprine [McNemar statistic 1.50 (p = 0.22), odds ratio 5.0 (95% confidence interval 0.6,236.5)]. Equal numbers of cases and controls (6% each) had taken cyclophosphamide and 18% of cases and 12% of controls had taken methotrexate [McNemar statistic 0.13 (p = 0.72), odds ratio 1.7 (0.3, 10.7)]. Results suggest but do not prove that RA patients taking azathioprine and methotrexate may have an increased risk of developing lymphoma. However, even if this increased risk can be confirmed, it accounts for only a small proportion of the greatly increased incidence of these malignancies in RA.