AbstractBackgroundCytomegalovirus (CMV) is associated with morbidity and mortality following allogeneic hematopoietic cell transplantation (alloHCT). Letermovir is a novel antiviral agent that prevents CMV reactivation in alloHCT patients, with limited data regarding influence on post‐alloHCT outcomes.MethodsWe retrospectively examined 273 alloHCT recipients, 158 in the non‐letermovir cohort (NLC), and 115 in the cohort using letermovir prophylaxis (LC). Patients that received letermovir were CMV‐seropositive and met criteria for high risk of CMV reactivation.ResultsMedian start of letermovir was 21 days post‐alloHCT, median duration of prophylaxis was 86 days. Letermovir prophylaxis demonstrated a statistically significant reduction in first CMV reactivation (at 200 days post 63.9% in the NLC vs. 35.7% in the LC; p < .001). On univariate analysis at 1 year, overall survival (OS) for NLC was 79.6% and 79.5% for LC (p = .54). Non relapse mortality (NRM) at 1 year for NLC was 12% and 12.3% for LC (p = .69). Cumulative incidence of relapse (CIR) at 1 year was 13.9% for NLC versus 17.1 for the LC (p = .27). On multivariable analysis, there was no significant difference between the two cohorts for OS, NRM, and CIR.ConclusionsLetermovir prophylaxis started at day +21 post‐alloHCT reduced CMV reactivation, with no impact on posttransplant outcomes.