The purpose of this study was to analyze different regimens of viral prophylaxis after combined pancreas-kidney transplantation (PKT). Over a 4-year period, we performed 82 PKTs with quadruple immuno-suppression with OKT3 induction. Four regimens of prophylaxis were studied. The first 30 patients received standard intravenous immunoglobulin (FVTG; 0.5 g/kg) for 6 doses and oral acyclovir for 3 months. The next 34 recipients received intravenous ganciclo-vir (2.5 mg/kg) twice daily for 2 weeks followed by oral acyclovir for 3 months. In the third group, patients were randomized to 5 doses over 2 months of either standard FVIG (n = 9) or CMV hyperimmune globulin (Cytogam; n = 9; 100–150 mg/kg) plus 2 weeks of IV ganciclovir followed by 3 months of oral acyclovir. The 4 groups were similar with respect to clinical, demographic, and immunologic variables, including donor and recipient CMV serologic status and blood transfusions. All patients were monitored for viral infections in the first 6 months after PKT. The regimens of prophylaxis resulted in (1) no major non-CMV (including no EBV) viral infections; (2) 3 cases of minor non-CMV viral infections (shingles); and (3) no differences in the incidence, timing, or severity of symptomatic CMV infections in the 4 groups. No death or graft loss was due to viral infection. Prophylaxis is effective in reducing the incidence of non-CMV viral infections and may reduce the severity of symptomatic CMV infection. However, we could not show any added benefit of either Cytogam or standard IVIG when used in combination with other antiviral agents. For economic as well as efficacy reasons, we recommend that IVIG preparations not be used routinely with antilymphocyte therapy but only in high-risk situations such as primary CMV exposure.