Background. The aim of the present study was to determine the influence of the venous drainage site on insulin homeostasis in simultaneous pancreas-kidney (SPK) transplant recipients. Methods. The study included 12 SPK patients with portal venous drainage (P) and 11 SPK patients with systemic venous drainage (S) of pancreas allograft. All of the participants presented similar characteristics. The euglycemic hyperinsulinemic clamp was performed using a 0.4-mU/kg/min insulin infusion. An infusion of [6,6-(2)H 2 ] glucose was used to determine glucose turnover at the basal state and during the clamp to determine liver and peripheral tissue sensitivity to insulin. Results. Minor changes in glycemia and insulinemia were shown: fasting plasma glucose was significantly higher in the SPK-P group and insulinemia was higher in the SPK-S group. Hepatic glucose production was similar in both groups. During the clamp, insulin levels were higher in SPK-S recipients, but hepatic glucose production was suppressed in both groups. Glucose use was lower in SPK-S recipients than in SPK-P recipients, 3.32±1.41 mg/kg/min and 4.70±1.64 mg/kg/ min, respectively (P