Background: Cytomegalovirus (CMV) is a major cause of serious morbidity following solid organ transplantation via both direct and indirect mechanisms. The aim of this study was to investigate the efficacy and safety of valacyclovir prophylaxis in heart transplant recipients. Methods:Twenty-seven CMV seropositive adults due to receive a heart transplant were included in a single-center, randomized, double-blind study. Patients were randomized to receive either oral valacyclovir 2000 mg or oral acyclovir 200 mg four times daily starting within 3 days of heart transplant and continuing for 90 days. The primary outcome measure was time to development of CMV antigenemia assessed for 6 months after surgery. Other measures were time to asymptomatic CMV infection, symptomatic CMV infections, and end-organ CMV disease. Patients were monitored for other herpes infections, other opportunistic infections, and acute graft rejection. Safety was assessed by evaluating changes in hematology and clinical chemistry parameters and by the occurrence of adverse events. Results:The median time to CMV antigenemia was 19 days for the acyclovir group compared with 119 days for the valacyclovir group (hazard ratio 0.42; 95% CI, 0.18-0.99; p = 0.049). Similar delays of approximately 100 days were found for CMV infection, symptomatic CMV infection, and CMV disease. There was also a trend for delayed acute rejection, and fewer opportunistic or other herpesvirus infections occurred in the valacyclovir group. Valacyclovir was well tolerated in the study population. Conclusion:Oral valacyclovir is a safe and effective mode of prophylaxis of CMV after heart transplantation. Copyright © 2002 International Society for Heart and Lung Transplantation.