In a retrospective study, the strategy of giving high-dose acyclovir (500 mg/m2 every 8 h intravenously) from day 5 before transplantation to day 30 after transplantation was evaluated in 266 cytomegalovirus (CMV)-seropositive autograft recipients. the incidence of CMV pneumonia was compared with that in 85 control patients who did not receive high-dose acyclovir. There was no significant difference in the incidence of CMV pneumonia between groups at day 100 (Kaplan-Meier estimates, 6.3% [acyclovir] vs. 7.7% [controls], P = .63) and day 200 after transplantation (7.6% vs. 13.1%, P = .32). The overall rate of patients who presented with CMV disease without preceding excretion from blood, urine, or throat was 77%. CMV pneumonia was fatal in 9 (56%) of 16 acyclovir recipients compared with 5 (63%) of 8 controls (P = 1.0). Survival after transplantation was not different between groups (P = .68). Thus, high-dose acyclovir does not appear to be effective for prevention of CMV disease after autologous transplantation.