© 2016, American College of Rheumatology Background: Hypersensitivity reactions (HSRs) can occur with any of the available biologic agents used to treat rheumatoid arthritis (RA). We compared drug-specific risks for HSRs among RA patients enrolled in the US Medicare program. Methods: Using Medicare data, we identified new users of infused infliximab, abatacept, rituximab, tocilizumab, golimumab, and injected biologic agents. After identifying HSRs using validated algorithms, for each biologic agent, we calculated the cumulative incidence over 6 months and the incidence rates (IRs) in 0–1, 2–14, and 15–30 days of administration. For each biologic agent administration, followup started on the infusion/injection date and ended at HSR, subsequent biologic agent administration, death, coverage loss, 30-day followup, or December 31, 2013, whichever occurred first. Adjusted robust Poisson regression was used to compare the HSR risks across biologic agents. A sensitivity analysis was conducted using a nested case-crossover design. Results: We identified 725,591 biologic agent administrations and 248 HSRs among 80,587 new users of biologic agents. Of these, 26.9% occurred in users of intravenous abatacept, 4.6% in rituximab, 5.8% in intravenous tocilizumab, 22.9% in infliximab, and 39.7% in injectable anti–tumor necrosis factor inhibitors (anti-TNFi). The cumulative incidence of HSRs over 6 months for all biologic agents was low (<1%).The IRs for HSRs ranged from 2.4 (abatacept) to 239.5 (rituximab) per 106 person-days. After adjustment, and using injectable anti-TNFi over 0–30 days as the referent, rituximab, infliximab, abatacept, and tocilizumab infusions were associated with a statistically significant higher risk of HSR. The sensitivity analysis yielded similar results. Conclusion: Among RA patients taking biologic agents, rituximab and infliximab were most strongly associated with HSRs. The absolute IRs of HSR events for all biologic agent exposures were low.