This study sought to determine whether high-dose acyclovir improves posttransplant survival in cytomegalovirus (CMV)-seropositive patients when ganciclovir is given for prophylaxis or as early therapy. Three groups were studied: Group 1 (n = 112) received ganciclovir from engraftment without prior acyclovir treatment, group 2 (n = 114) was given ganciclovir for CMV pp65 antigenemia without prior acyclovir, and group 3 (n = 133) received ganciclovir at engraftment with prior intravenous acyclovir (500 mg/m2 every 8 h) from day 5 before transplant until engraftment. In a multivariable Cox model, there was no significant difference in the adjusted risk of transplant survival between the groups during the first 2 years after transplant (relative risk for mortality: group 1, 1.0; group 2, 0.75 (95% confidence interval [CI], 0.52-1.1); group 3, 1.04 (95% CI, 0.74-1.47). The incidence of CMV disease and CMV-related mortality was not significantly different between the groups. Thus, high-dose acyclovir does not appear to improve survival when ganciclovir is given either at engraftment or for CMV pp65 antigenemia.