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CMV seropositive (R+) hematopoietic cell transplant (HCT) recipients have a survival disparity compared with CMV seronegative recipient/donor (R-D-) pairs. We hypothesized that primary letermovir prophylaxis (LET) may abrogate this disparity. We investigated the relationship between LET and mortality at 1year post-HCT.In this retrospective cohort study, we included adult R-D- or R+ patients who received HCT pre-LET (between January 1, 2013 through December 15, 2017) and post-LET (between December 16, 2017 through December 2019). R+ were categorized by LET receipt as R+/LET or R+/no-LET. Cox proportional hazard models were used to estimate the association of LET with all-cause mortality at one-year post-transplantation.Of 848 patients analyzed, 305 were R-D-, 364 R+/no-LET and 160 R+/LET. Because of similar mortality (adjusted hazard ratio [aHR] [95% confidence interval]); 1.29 [0.76-2.18; p=0.353] between pre-LET/R-D- and post-LET/R-D-, R-D- were combined into one group. Compared with R-D-, the aHR for mortality was 1.40 [1.01-1.93] for R+/no-LET and 0.89 [0.57-1.41] for R+/LET. Among R+, LET was associated with decreased risk of death (aHR 0.62 [0.40-0.98]); when conventional and T-cell depleted HCT were analyzed separately, the aHR was 0.86 [0.51-1.43] and 0.21 [0.07-0.65] respectively.At one-year post HCT, LET was associated with closing the mortality disparity between R-D- and R+. Among all R+, LET was associated with decreased mortality; driven by 79% reduced incidence of death in T-cell depleted HCT.