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Subgroups of patients with inflammatory bowel disease (IBD) may have an increased risk of developing lymphoma. We sought to identify factors that were associated with lymphoma in patients with IBD.Cases and controls were identified through a centralized diagnostic index. We identified 80 adult patients with IBD who developed lymphoma between 1980 and 2009. For each case, 2 controls were matched for subtype of IBD, geographic location, and length of follow-up. Conditional logistical regression was used to assess associations between risk factors and the development of lymphoma.Sixty patients were males (75%) versus 77 controls (48%). Median age at index date was 59 years for cases and 42 years for controls. Twenty patients (25%) and 23 controls (14%) were receiving immunosuppressive medications at the index date. Four patients (5%) and 6 controls (4%) were receiving anti–tumor necrosis factor α agents at the index date. In multiple variable analysis, age per decade (odds ratio, 1.83; 95% confidence interval, 1.37–2.43), male gender (odds ratio, 4.05; 95% confidence interval, 1.82–9.02) and immunosuppressive exposure at the index date (odds ratio, 4.20; 95% confidence interval, 1.35–13.11) were significantly associated with increased odds of developing lymphoma. Disease severity and use of anti–tumor necrosis factor α agents were not independently associated with developing lymphoma. When testing was performed on patients exposed to immunosuppressive or anti–tumor necrosis factor α medications, Epstein–Barr virus was identified 75% of the time.In this case–control study, increasing age, male gender, and use of immunosuppressive medications were associated with an increased risk of lymphoma in patients with IBD.