As cytomegalovirus (CMV) disease was a leading cause of death following liver transplantation in earlier reports, general CMV prophylaxis is widely used. We re-evaluated the impact of CMV in a recent time period under balanced immunosuppression and effective CMV diagnostics and therapy. A retrospective analysis of 1200 liver transplantations between 1988 and 2000 was performed comparing the incidence of CMV infection and disease and patient survival rates in two different time periods (before and after availability of the pp65-antigenaemia assay). In addition, risk factors for CMV in the recent time period were analysed. No ganciclovir prophylaxis was administered during the whole study period. The incidence of CMV tissue invasive disease decreased from 9.4% in period I to 2.7% in period II, whereas the incidence of viral syndrome was about 6% in both periods. Especially CMV pneumonia and generalized disease were almost abandoned in period II. Patients with tissue invasive disease, but not with infection or viral syndrome had reduced survival rates in both periods. However, the disease-specific mortality was 10% and 0% respectively. The overall rate of CMV infection in period II was low (25.9%). Risk factors for CMV infection in the univariate analysis were: Initial nonfunction, D+R− seroconstellation, acute liver failure, triple or quadruple immunosuppression, OKT3 or ATG treatment, transfusion of >10 packed red cells, steroid boluses, postoperative mechanical ventilation and retransplantation. In the multivariate analysis only quadruple or triple immunosuppression, OKT3-treatment, transplantation for acute liver failure and initial nonfunction. The incidence of CMV tissue invasive disease as well as the disease-specific mortality has markedly decreased during the last years. Using routine surveillance with the pp65-antigenaemia assay, CMV infection and disease rates compare well to data with long-term ganciclovir prophylaxis. As D+R− patients still more often develop symptomatic disease, pre-emptive therapy could be useful in this patient group.