Cytomegalovirus (CMV) is a substantial cause of morbidity in pulmonary allograft recipients. In an attempt to decrease the prevalence of this infection, we treated 13 recipients at risk for cytomegalovirus with 3 wk of intravenous ganciclovir (5 mg/kg twice a day for 14 days, starting 5 days after the procedure, followed by 1 wk of the drug at a dose of 5 mg/kg/day). Following the ganciclovir course, patients received oral acyclovir, 800 mg three times a day for at least 2 months more. CMV infections developed in 5 recipients (38%), and none of these episodes occurred during the ganciclovir therapy. Neither of the 2 deaths in this group could be attributed to CMV. In comparison, the prevalence of CMV in the preceding cohort of 11 transplant recipients who were administered acyclovir alone was 91% (p << 0.01 by log- rank test), and there were 3 deaths due to viral infections (p = 0.08 by Fisher's exact test). Groups were similar in terms of immunosuppression and renal function during treatment, and none of the recipients developed leukopenia. We conclude that ganciclovir prophylaxis is well tolerated and appears to have considerable efficacy for prevention of CMV infections in pulmonary transplant recipients.