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This study compared the pre-emptive and the prophylactic strategies used to prevent cytomegalovirus (CMV) infection and disease in CMV-seropositive orthotopic liver-transplant recipients and searched for associated predictive factors. Seventy-three orthotopic liver-transplant recipients who had received a transplant before November 2005 were given ganciclovir IV pre-emptively (group I) and 56 recipients who had received a transplant after November 2005 were given prophylactic valganciclovir for 3 months (group II). Demographic and biochemical parameters did not statistically vary between the groups at baseline. Monitoring of CMV DNAemia was similar in both groups. Forty-two (57.5%) patients presented with CMV infection in group I and 18 (32.1%) in group II (P < 0.004). CMV DNAemia was first detected at a median of 33 days post-transplant in group I and at 98.5 days in group II (P < 0.003), but viral loads were not significantly different. The overall incidence of CMV disease was 9.6% in group I versus 7.1% in group II (ns). Thirty-five (47.9%) patients presented with biopsy-proven acute rejection in group I and 13 (23.2%) in group II (P = 0.004). Forty (55%) patients in group I and 25 (44.6%) in group II presented with de novo post-transplant diabetes (P = 0.057). At 1-year post-transplant, global survival curves were not significantly different. Independent factors associated with CMV reactivation were an absence of CMV prophylaxis, CMV serological status of the donor, cold ischemia time, and HLA A + B + DR compatibility. CMV prophylaxis is efficacious and can prevent safely the direct and indirect effects of CMV infection in CMV-seropositive orthotopic liver-transplant recipients. J. Med. Virol. 87:836–844, 2015. © 2015 Wiley Periodicals, Inc.