Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly expanded; however, clinical trials excluded patients taking immunosuppressive medications such as those with inflammatory bowel disease (IBD). Therefore, we explored real-world effectiveness of coronavirus disease 2019 (COVID-19) vaccination on subsequent infection in patients with IBD with diverse exposure to immunosuppressive medications. This was a retrospective cohort study of patients in the Veterans Health Administration with IBD diagnosed before December 18, 2020, the start date of the Veterans Health Administration patient vaccination program. IBD medication exposures included mesalamine, thiopurines, anti-tumor necrosis factor biologic agents, vedolizumab, ustekinumab, tofacitinib, methotrexate, and corticosteroid use. We used inverse probability weighting and Cox’s regression with vaccination status as a time-updating exposure and computed vaccine effectiveness from incidence rates. The cohort comprised 14,697 patients, 7321 of whom received at least 1 vaccine dose (45.2% Pfizer, 54.8% Moderna). The cohort had median age 68 years, 92.2% were men, 80.4% were White, and 61.8% had ulcerative colitis. In follow-up data through April 20, 2021, unvaccinated individuals had the highest raw proportion of SARS-CoV-2 infection (197 1.34% vs 7 0.11% fully vaccinated). Full vaccination status, but not partial vaccination status, was associated with a 69% reduced hazard of infection relative to an unvaccinated status (hazard ratio, 0.31, 95% confidence interval, 0.17–0.56; P < .001), corresponding to an 80.4% effectiveness. Full vaccination (> 7 days after the second dose) against SARS-CoV-2 infection has an ∼80.4% effectiveness in a broad IBD cohort with diverse exposure to immunosuppressive medications. These results may serve to increase patient and provider willingness to pursue vaccination in these settings.