© 2018, American College of Rheumatology Objective: Multiple studies have shown seemingly unfavorable changes in lipid profiles associated with interleukin-6 receptor (IL-6R) antagonists and some other therapies for rheumatoid arthritis. The aim of this study was to assess the real-world cardiovascular disease (CVD) risk associated with tocilizumab, the first anti–IL-6R medication approved for the treatment of RA. Methods: We conducted a cohort study using 2006–2015 Medicare and MarketScan claims for patients with RA in whom treatment with biologic disease-modifying antirheumatic drugs was initiated after January 1, 2010. The primary outcome was a composite of myocardial infarction, stroke, and fatal CVD, assessed using a validated method. The influence of potential confounding due to RA disease activity was assessed in a subgroup analysis (~5–10% of biologic therapy initiations) using the multi-biomarker disease activity (MBDA) score. Results: A total of 88,463 patients with RA were included. The crude incidence rate (IR) per 1,000 patient-years for composite CVD events among Medicare patients ranged from 11.8 (95% confidence interval [95% CI] 9.7–14.4) for etanercept users to 17.3 (95% CI 15.2–19.7) for infliximab users. The crude IR for pooled users of a tumor necrosis factor inhibitor was 15.0 (95% CI 13.9–16.3). Compared to tocilizumab, the corresponding adjusted hazard ratios (HRs) were 1.01 (95% CI 0.79–1.28) for abatacept, 1.16 (95% CI 0.89–1.53) for rituximab, 1.10 (95% CI 0.80–1.51) for etanercept, 1.33 (95% CI 0.99–1.80) for adalimumab, and 1.61 (95% CI 1.22–2.12) for infliximab. There were no statistically significant differences in the risk of CVD between tocilizumab and any other biologic when MarketScan data were used. Results were robust in numerous subgroup analyses and after external adjustment to control for RA disease activity in the subgroup of patients with linked MBDA test results (n = 4,156). Conclusion: Tocilizumab was associated with a CVD risk comparable to that for etanercept as well as a number of other biologics used for the treatment of RA.