Cytomegalovirus (CMV)-seronegative liver transplant recipients with CMV-seropositive donors have the greatest risk for CMV disease. We performed a randomized, controlled trial comparing sequential intravenous (IV) and oral ganciclovir with prolonged IV ganciclovir for long-term prophylaxis of CMV disease in these high-risk patients. Patients were initially given IV ganciclovir at a dose of 6 mg/kg per day from days 1 to 14 after transplantation. Patients then either received oral ganciclovir (1 g every 8 hr) or continued IV ganciclovir (6 mg/kg once per day on Monday-Friday of each week) from days 15 to 100 after transplantation. CMV disease occurred in 3 of 32 patients (9.3%) receiving oral ganciclovir and in 4 of 32 patients (12.5%) receiving IV ganciclovir within the first year after transplantation (P>0.2). All cases of CMV disease occurred more than 90 days after transplantation (median time of onset day +137 for oral ganciclovir and day +135 for IV ganciclovir). There were no deaths from CMV in either study group. Both oral and IV ganciclovir were generally well tolerated. These results indicate that, after induction with 14 days of IV ganciclovir, oral ganciclovir can be as effective as IV ganciclovir for long-term prophylaxis of CMV disease in high-risk CMV-seronegative liver transplant recipients with CMV-seropositive donors and eliminates the need for prolonged IV access.