To determine the impact of high-dose oral acyclovir on cytomegalovirus (CMV) infection or disease after liver transplantation, CMV cultures were prospectively collected for 6 months after transplantation. The incidence and timing of infection and disease in patients receiving high-dose oral acyclovir (3200 mg/day) from day 7 until 3 months after transplantation were compared with an historical control group who received no acyclovir. All patients who did not receive acyclovir (group 1, n = 12) but only 57% of those who did (group 2, n = 22) had CMV infection (P = .008). Nine (75%) group 1 but only 3 (14%) group 2 patients had positive leucocyte cultures (P = .0007). Three group 1 patients developed CMV disease; 1 group 2 patient developed CMV hepatitis. Each of these 4 patients had CMV viremia (P = .01). The frequency of CMV infection after liver transplantation appears to be reduced by high-dose oral acyclovir.