Simultaneous pancreas-kidney transplantation (SPKT) improves long-term survival of insulin-dependent diabetes mellitus patients with diabetic nephropathy. The increasing success of SPKT is a result of improved surgical technique, better organ preservation, potent antirejection therapy, and effective use of antibiotics to prevent and treat infectious complications. However, morbidity and mortality following SPKT remain high mainly owing to infection. From 1988 to 2004, the 51 patients who underwent SPKT were 32 women and 19 men of mean age 34 +/- 4 years old with diabetes and end-stage renal disease. The mean duration of diabetes mellitus was 23 +/- 4 years. The incidence of HCV and HBV infections were 19.6% and 13.7%, respectively. Preoperative work-up included identification and elimination prior to surgery of potential sources of infection. All patients prior to SPKTx had been treated by dialysis (26 +/- 20 months). The kidneys were always placed into the left retroperitoneal space first; at the same time the pancreatic grafts were prepared on the back table. The reconstruction of the superior mesenteric and the splenic arteries was performed using a Y graft of donor iliac artery to the common or external donor's iliac artery. The pancreas was transplanted intraperitoneally to the right iliac vessels. The portal vein was sutured to the common or external iliac vein and the arterial conduit of donor iliac artery. In 20 of the patients, bladder drainage and in 31, enteric drainage was used for the pancreatic juice exterioration. Patients received immunosuppression with a calcineurin inhibitor (tacrolimus or cyclosporin), mycophenolic acid or azathioprine, and steroids. Antibody induction (alternatively anti-IL-2 monoclonal antibody or ATG) was used in last 38 patients. Antibacterial (tazobactam) and antifungal (fluconazole) as well as antiviral (gancyclovir) prophylactic treatment was given to all patients for 7 to 10 days after transplantation. Thirty-eight recipients are alive, 26 with function of both grafts; 8 with functioning kidney grafts; and 4 with nonfunctioning grafts on dialysis treatment from 1 to 14 years after transplantation. Thirteen patients (24.5%) died during the first year after transplantation. Infectious complications were the main cause of death. Systemic infections accounted for the death of five patients and CNS infection for death of another five patients. Three patients died with functioning grafts due to cardiopulmonary disorders (myocardial infarction, pulmonary embolus) early in the postoperative period. A total of 102 infections were diagnosed in 51 patients during the posttransplant course. Twenty-one episodes of CMV infection (systemic 20, duodenal site 1), 73 bacterial infections (systemic 13, pulmonary 13, urinary tract 15, intestinal 8, wound 23), and 8 fungal infections (central nervous system 5, gastrointestinal tract 3). Some patients had more than one type of infection. Overall mortality in the investigated group was 24.5%. Infectious complications were the main cause of death (77%), including systemic infection (38.5%) and CNS infection (38.5%). The predominant etiology of the systemic infections was bacterial. The etiology of CNS infections was fungal. In conclusion, infectious complications are the main cause of morbidity and mortality following SPKT. The early diagnosis of infection, particularly fungal complications, is necessary. The administration of broad-spectrum prophylactic antibiotics, antifungal, and antiviral agents is recommended.