BACKGROUND Previous studies have questioned the safety of vascularized pancreas transplantation (PTX), particularly because diabetes is an independent risk factor for coronary artery disease and cardiac death. METHODS A retrospective analysis of the timing and causes of death after PTX was performed. From April 1989 through December 1995, 196 PTXs were performed in 186 diabetic patients including 134 simultaneous kidney-PTXs, 59 solitary PTXs, and 3 combined liver-PTXs. All patients underwent whole organ PTX with bladder drainage, received triple or quadruple immunosuppression, and had a minimum follow-up of 1 year (mean 3.8 years). RESULTS A total of 22 patients (12%) died at a mean of 19 months after PTX. Infection was the most common cause of early death, whereas the majority of late deaths were due to cardiac causes. In the 8 deaths caused by infection, 6 were associated with operative complications, but only 2 received excessive immunosuppression for rejection. In the 10 cardiac deaths, 6 patients were older than 40 years at the time of PTX and 4 had experienced pancreas graft loss before death. Four-year actuarial patient survival was 92% after simultaneous kidney-PTX and 87% after solitary PTX. CONCLUSIONS In this series, the mortality rate after PTX was 12%, with infection, myocardial infarction, and sudden death accounting for over 80% of deaths. Deaths from infection most commonly occurred early and were associated with operative complications, whereas cardiac deaths usually were late and related to recipient age or preceded by pancreas graft loss. Future strategies aimed at reducing mortality after PTX should emphasize appropriate recipient selection and target prevention of operative complications.