Background-There is concern that selective serotonin reuptake inhibitors (SSRIs) substantially increase bleeding risk in patients taking anticoagulants. Methods and Results-We studied 737 patients taking SSRIs in the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Embolism and Stroke Trial in Atrial Fibrillation) trial of rivaroxaban compared with warfarin for the prevention of stroke/systemic embolism in patients with atrial fibrillation. These patients were propensity score matched 1: 1 to 737 patients not taking SSRIs. The primary outcome measure was major and nonmajor clinically relevant bleeding events, the principal safety outcome in ROCKET AF. Over a mean 1.6 years of follow-up, the rate of major/nonmajor clinically relevant bleeding was 18.57 events/100 patient-years for SSRI users versus 16.84 events/100 patient-years for matched comparators, adjusted hazard ratio (aHR) of 1.16 (95% confidence interval [CI], 0.95- 1.43). The aHRs were similar in patients taking rivaroxaban (aHR 1.11 [95% CI, 0.82-1.51]) and those taking warfarin (aHR 1.21 [95% CI, 0.91-1.60]). For the rarer outcome of major bleeding, the aHR for SSRI users versus those not taking SSRIs was 1.13 (95% CI, 0.62-2.06) for rivaroxaban; for warfarin, the aHR was higher, at 1.58 (95% CI, 0.96-2.60) but not statistically significantly elevated. Conclusions-We found no significant increase in bleeding risk when SSRIs were combined with anticoagulant therapy, although there was a suggestion of increased bleeding risk with SSRIs added to warfarin. While physicians should be vigilant regarding bleeding risk, our results provide reassurance that SSRIs can be safely added to anticoagulants in patients with atrial fibrillation.