Objective To estimate the incidence and risk factors for gastrointestinal (GI) perforation among patients with rheumatoid arthritis (RA). Methods Claims from employer health insurance plans were used to identify RA patients and those hospitalized for upper or lower GI perforation. GI perforation cases were identified using both a sensitive and a specific definition. A Cox model using fixed and time-varying covariates was used to evaluate the risk of GI perforation. Results Among 143,433 RA patients, and using a maximally sensitive GI perforation definition, 696 hospitalizations with perforation were identified. The rate of perforation was 1.70 per 1,000 person years (PYs; 95% confidence interval [95% CI] 1.58-1.83), and most perforations (83%) occurred in the lower GI tract. The rate of perforation was lower when a more specific GI perforation definition was used (0.87; 95% CI 0.78-0.96 per 1,000 PYs). Age and diverticulitis were among the strongest risk factors for perforation (diverticulitis hazard ratio [HR] 14.5 [95% CI 11.8-17.7] for the more sensitive definition, HR 3.9 [95% CI 2.5-5.9] for the more specific definition). Among various RA medication groups and compared to methotrexate, the risk of GI perforation was highest among patients with exposure to nonsteroidal antiinflammatory drugs (NSAIDs), concomitant nonbiologic disease-modifying antirheumatic drugs, and glucocorticoids. Biologic agents without glucocorticoid exposure were not a risk factor for perforation. Conclusion GI perforation is a rare but serious condition that affects patients with RA, most frequently in the lower GI tract. Clinicians should be aware of risk factors for GI perforation when managing RA patients, including age, history of diverticulitis, and use of glucocorticoids or NSAIDs. © 2012 by the American College of Rheumatology.