Abstract New antiviral agents and practice guidelines have been implemented to address cytomegalovirus (CMV) infection in organ transplantation. We hypothesized that such measures would reduce rates of symptomatic CMV infection, CMV disease, and CMV seroconversion and associated complications in renal transplant and simultaneous pancreas-kidney transplant recipients. We analyzed the impact of CMV in 1,424 renal transplant and simultaneous pancreas-kidney transplant recipients, transplanted at our center between January 1, 1994 and June 30, 1999. Most patients received quadruple sequential immunosuppression with high-dose acyclovir (800 mg four times daily) for 12 weeks as prophylaxis. High-risk patients (donor CMV-positive/recipient CMV-negative) received ganciclovir (500 to 1,000 mg three times daily) beginning in 1998, again for 12 weeks. One hundred and one renal transplant (9.0%) and 40 simultaneous pancreas-kidney transplant (13.4%) recipients experienced symptomatic CMV infection or CMV disease. Donor CMV-positive/recipient CMV-negative patients had the greatest rates of CMV infection or CMV disease (25.2%; P = 0.0001 versus all other categories). The impact of CMV on outcomes was evaluated in a proportional hazards model. Symptomatic CMV infection or CMV disease increased the risk for subsequent rejection (relative risk, 2.11; P = 0.003) and non-CMV infection (relative risk, 2.24; P = 0.001). To determine if the effects of ganciclovir were masked by pre-1998 data, CMV infection and CMV disease rates for ganciclovir-treated patients (n = 62) were censored at 1 year and compared with acyclovir-treated patients (n = 287). Ganciclovir was associated with trends toward lower rates of infection and disease. It also delayed the time to infection or disease. Serologic testing in high-risk patients also showed late seroconversion, with 20% of patients seroconverting by 6 months, 12 weeks after the prophylaxis period. These data suggest that despite better prophylaxis strategies, CMV remains an important pathogen in renal transplant and simultaneous pancreas-kidney transplant recipients. This finding may require reassessment of prophylaxis strategies and the development of alternative or novel anti-CMV regimens. © 2002 by the National Kidney Foundation, Inc.