BACKGROUND: Serotonin reuptake inhibitor (SRI) antidepressants have known antiplatelet properties. Patients with hematologic malignancies (HMs) are at an increased risk of bleeding complications due to their malignancy and treatment-induced thrombocytopenia. OBJECTIVE: The purpose of this study was to evaluate the risk of clinically significant bleeding (CSB) in patients with HM and thrombocytopenia who are prescribed SRIs. METHODS: This retrospective cohort study included adult patients admitted to the hospital with HM and thrombocytopenia. Patients were stratified into SRI-exposed and SRI-unexposed groups. Patients were followed up until resolution of thrombocytopenia, hospital discharge, death, or SRI therapy interruption. The primary outcome was the incidence of CSB. RESULTS: A total of the 324 patients were included in the study (119 SRI exposed vs 205 SRI unexposed). The median baseline platelet value was 35 × 10 CONCLUSION AND RELEVANCE: In patients with HM and thrombocytopenia, SRI exposure was not associated with an increased risk of CSB. Given the small study size, assessment of patient-specific risks versus benefits should still be considered when prescribing SRI therapy in this patient population.