The infectious complications following pancreatic transplantation in 34 consecutive recipients were analyzed during a mean follow-up of 39 months. Twenty-seven recipients (79%) developed a mean of 2.1 serious infectious complications. Three of the six deaths (overall mortality, 18%) were infection related. Thirty-three percent of severe infectious episodes were caused by bacteria (72% by gram-positive cocci) and 26% by fungi (87% by Candida species); severe cytomegalovirus (CMV) infection accounted for 33% of infectious complications. CMV disease and organ involvement occurred most frequently in the donor-seropositive/recipient-seronegative group (36%), followed by the donor-seronegative/recipient-seropositive group (25%). In four patients (12%) Epstein-Barr virus (EBV)-related posttransplantation lymphoproliferative disease (PTLD) developed, directly resulting in two deaths. PTLD developed in two of the three EBV-seronegative and two of the 31 EBV-seropositive recipients. Infections due to herpes simplex and zoster viruses and Pneumocystis carinii (2, 3, and 1, respectively) developed in 6 patients. The use of OKT3 for rejection therapy was associated with symptomatic CMV disease and EBV-related PTLD. In summary, severe infectious complications are the main cause of morbidity and death among patients who undergo pancreas transplantation. Aggressive antimicrobial prophylactic regimens are required to decrease the effects of such complications.