Reactivation of the cytomegalovirus (CMV) following allogeneic hematopoietic cell transplant (HCT) is one of the most common viral consequences, and it can cause severe morbidity and mortality. In clinical studies of CMV-seropositive HCT recipients, primary prophylaxis with letermovir reduced clinically significant CMV infections (CS-CMVi). For a study, researchers wanted to determine how primary letermovir prophylaxis affects the incidence and consequences of refractory or resistant CMV infections in this cohort. The researchers did a retrospective cohort analysis of 537 CMV-seropositive allogeneic HCT patients who were treated between March 2016 and October 2018. The electronic medical record collected baseline demographics, HCT features, CMV infections, therapy, and mortality data. CMV outcomes were determined using recently accepted clinical trial definitions. Characteristics and results were evaluated based on whether or not the participants had received main letermovir prophylaxis. During the first 100 days following HCT, 123 patients received letermovir for primary prophylaxis, while 414 did not. In a multivariate analysis, primary letermovir prophylaxis was linked to lower rates of CS-CMVi (HR 0.26; 95% confidence interval [CI], 0.16–0.41), CMV end-organ disease (HR 0.23; 95% CI, 0.10–0.52), refractory or resistant CMV infection (HR 0.15; 95% CI, 0.04–0.52), and non-relapse mortality at week 48 (HR 0.55; 95% CI, In the first letermovir prophylaxis group, there was no resistant CMV or CMV-related mortality. Primary letermovir prophylaxis significantly avoids refractory or resistant CMV infections, as well as CS-CMVi and CMV illness after allogeneic HCT, and reduces non-relapse mortality at week 48.