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.