Abstract: PURPOSE/BACKGROUND: Treatment-emergent bleeding is a well-known risk with serotonergic antidepressants. Studies assessing this risk based on varying serotonergic binding affinity are limited. This report was conducted to address this gap in the literature by evaluating antidepressant-associated bleeding risks based on binding affinity to the serotonin transporter (SERT). METHODS/PROCEDURES: A sample of bleeding events from 267 patients that occurred between January 1, 2018 and January 1, 2020, within a single Veterans Affairs (VA) Health Care System was retrospectively evaluated. The primary endpoint was the percentage of veterans experiencing a bleeding event while prescribed an antidepressant with high (Ki ≤1), intermediate (Ki >1 to <10), or low (Ki ≥10) SERT binding affinity. FINDINGS/RESULTS: Approximately 56% of veterans who developed a bleed were prescribed an antidepressant with high SERT binding affinity compared with 17.2% and 26.6% among those receiving antidepressants with intermediate and low SERT binding affinity, respectively (P < 0.0001). The most common bleeding types were hematuria, upper gastrointestinal bleeds, and hematologic dyscrasias. IMPLICATIONS/CONCLUSIONS: The results suggest that veterans receiving antidepressants with high binding affinity to SERT are at a significantly higher risk of bleeding. Larger randomized prospective trials are necessary to fully elucidate these findings.