Objective: To evaluate the long-term safety of rituximab in an observational cohort of patients with rheumatoid arthritis (RA) who had an inadequate response to ≥1 anti–tumor necrosis factor therapy in the US (SUNSTONE [Study of the Safety of Rituxan in Patients With Rheumatoid Arthritis After an Inadequate Response to Previous Anti-TNF Therapy] registry). Methods: In this prospective, observational cohort study, patients received rituximab according to their physician's standard practice and were evaluated at standard-of-care follow-up visits at least every 6 months. The primary outcome was the incidence of protocol-defined significant infections. Secondary outcomes included serious adverse events potentially associated with rituximab, cardiovascular or thrombotic events, seizures, deaths, and pregnancies. Post hoc analyses assessed outcomes by concomitant medication use. Results: Overall, 989 patients (safety-evaluable population) received ≥1 dose of rituximab, with a total follow-up of 3,844 patient-years (mean duration 3.9 years). In total, 341 significant infections occurred in 197 patients (19.9%). The incidence rates (95% confidence intervals [95% CIs]) for significant infections, cardiovascular or thrombotic events, and seizures were 8.87 (95% CI 7.98–9.86), 1.95 (95% CI 1.56–2.45), and 0.18 (95% CI 0.09–0.38) per 100 patient-years, respectively. The incidence of significant infections did not increase with time or with cumulative rituximab exposure. During the study, 64 patients died (crude mortality rate 1.66 per 100 patient-years [95% CI 1.30–2.13]). The most common causes of death were infections (n = 19), malignancy (n = 14), and cardiovascular events (n = 13). Eight pregnancies were reported in 7 patients. Conclusion: In patients with RA treated with rituximab for up to 5 years, the rates of significant infections were stable over time and higher in patients who received long-term systemic steroid treatment.