The impact of cytomegalovirus (CMV) serostatus (seropositive [⁺] or seronegative [^-]) of the donor (D) and recipient (R) on mortality after allogeneic non-T cell-depleted stem cell transplantation (SCT) in the era of preemptive therapy was assessed among 1750 patients by means of multivariable Cox regression models. In an analysis that included only pre-SCT variables, D⁺/R⁺ and D⁺/R^- patients had the highest risk for mortality. After neutropenia or the occurrence of CMV disease was controlled for, only D⁺/R^- patients remained at a significantly higher risk for mortality. Mortality due to bacteremia or invasive fungal infection was higher among D⁺/R^- (18.3%) than D^-/R^- (9.7%) patients (P < .001). Thus, CMV serostatus remains associated with mortality; neutropenia due to ganciclovir administration and CMV disease explain the association with mortality among seropositive recipients. However, in D⁺/R^- subjects, mortality appears to be associated with bacterial and fungal infection, indicating a possible immunomodulatory effect of primary CMV infection that was undetected despite intensive monitoring.