BACKGROUND : Depression and coronary artery disease (CAD) are leading causes of death and disability and commonly co-occur. Different antidepressant classes have similar efficacy for depressed patients with CAD, but cardiovascular implications are unclear. Selective serotonin reuptake inhibitors (SSRIs) and mirtazapine are first-line options for depressed patients with CAD. SSRIs, but not mirtazapine, have known antiplatelet effects. Whether this affects risk of bleeding and major adverse cardiac events (MACE) in patients requiring dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) is unknown. OBJECTIVE : The aim of this analysis is to examine the impact of SSRI treatment on the co-primary endpoints of composite MACE (death, myocardial infarction, or stroke) and composite bleeding events in patients treated with clopidogrel-based DAPT after PCI. METHODS : We conducted a retrospective study with co-primary endpoints of bleeding and MACE within 1 year of PCI. Three groups were compared: SSRI patients, mirtazapine patients, and patients on neither agent. Mirtazapine acted as a comparator to control for depression, for which diagnosis coding was inadequate. Time-to-event analyses were performed with Kaplan-Meier estimators and adjusted analyses utilized Cox proportional hazards. There were 6874 (820 SSRI, 55 mirtazapine, 5999 neither) patients included. RESULTS : SSRI patients had lower MACE risk than mirtazapine patients (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.38-0.97, p = 0.036) but higher MACE risk than patients on neither agent (HR 1.21, 95% CI 1.02-1.43, p = 0.030) in adjusted analyses. No significant differences were associated with bleeding risk (SSRI vs. neither adjusted HR 1.07, 95% CI 0.93-1.24, p = 0.36). CONCLUSIONS : SSRI use was associated with a significant decrease in MACE rates compared with patients receiving mirtazapine. Bleeding risk was not affected by either antidepressant treatment. SSRIs may have cardioprotective benefits compared with mirtazapine.