AbstractBackgroundLeukopenia in the early period following heart transplantation (HT) is not well‐studied. The aim of this study was to evaluate risk factors for the development of post‐transplant leukopenia and its consequences for HT recipients.MethodsAdult patients at a large‐volume transplant center who received HT between January 1, 2010 and December 31, 2020 were included. The incidence of leukopenia (WBC ≤3 × 10³/μL) in the first 90‐days following HT, individual risk factors, and its effect on 1‐year outcomes were evaluated.ResultsOf 506 HT recipients, 184 (36%) developed leukopenia within 90‐days. Median duration of the first leukopenia episode was 15.5 days (IQR 8–42.5 days). Individuals who developed leukopenia had lower pre‐transplant WBC counts compared to those who did not (6.1 × 10³/μL vs. 6.9 × 10³/μL, p = .02). Initial immunosuppressive and infectious chemoprophylactic regimens were not significantly different between groups. Early leukopenia was associated with a higher mortality at 1‐year (6.6% vs. 2.1%, p = .008; adjusted HR 3.0) and an increased risk of recurrent episodes. Rates of infection and rejection were not significantly different between the two groups.ConclusionsLeukopenia in the early period following HT is common and associated with an increased risk of mortality. Further study is needed to identify individuals at highest risk for leukopenia prior to transplant and optimize immunosuppressive and infectious chemoprophylactic regimens for this subgroup.