Clinically, the incidence of reversible renal allograft rejection episodes appears to be higher in recipients of simultaneous pancreas/kidney (SPK) than of kidney transplantation alone (KTA); conversely, the rate of irreversible pancreas allograft rejection appears to be higher in pancreas transplant alone (PTA) than SPK recipients. Clinical/histological correlation of graft rejection in these three groups has not been precise. Therefore, we studied the incidence and histological severity of the rejection process in a large animal (pig) model of SPK (n = 36), PTA (n = 31), and KTA (n = 36) allotransplantation. SPK and PTA recipients were made diabetic pretransplant by streptozotocin (150 mg/kg). Pancreas graft exocrine secretions were bladder-drained via a duodenocystostomy for urine amylase (UA) monitoring; endocrine function was monitored by plasma glucose (PG) levels. SPK and KTA recipients underwent native nephrectomy, and renal allograft function was monitored by serum creatinine (OR). Cyclosporine, azathioprine, and prednisone were given in tapering doses from the time of transplantation. Grafts were biopsied weekly to grade histologic severity of interstitial and vascular rejection on light microscopy (LM) and for intensity of T cell infiltration on immunofluorescence. Pancreas graft exocrine function (UA above pretransplant baseline), present in 62% of PTA and 68% of SPK recipients at one week, persisted in only 7% of PTA vs. 64%. of SPK pigs at 2 weeks (P = 0.0004). Likewise, pancreas graft endocrine function (PG <200 mg/dl off insulin) was sustained longer in SPK than PTA recipients (100% vs. 84% at 1 and 91% vs. 27% at 2 weeks; P = 0.0006). However, renal allograft functional survival (serum creatinine <3.0 mg/dl) was not significantly different (P = 0.471) between SPK and KTA recipients (36% vs. 30% at 1 and 23% vs. 13% at 2 weeks). Graft functional parameters partially correlated with biopsy observations. Pancreas allograft biopsies showed a significantly (P = 0.03 at 1 and P = 0.05 at 2 weeks) lower incidence of moderate/severe interstitial rejection in SPK than PTA recipients (67% vs. 95% at 1 and 57% vs. 92% at 2 weeks); rejection was absent in 8% of SPK and in no PTA biopsies at 1 week. Vascular rejection was moderate/severe in significantly fewer (P = 0.0013 at 1 and P = 0.023 at 2 weeks) SPK than PTA pancreas grafts (13% vs. 37% at 1 and 14% vs. 38% at 2 weeks). Immunofluorescent assessment of T lymphocytes and macrophages in pancreas grafts showed the frequency of moderate/severe infiltration to be less for both cell types at I week, respectively, 14% and 25% in SPK vs. 71% and 57% in PTA recipients. Pancreas graft destruction was less prominent in SPK than in PTA recipients (% of islet cells staining positive for insulin at 1 week 54% vs. 49%; P = 0.05). MHC class II antigen expression in acinar and ductal epithelium, virtually absent in normal pancreas, was prominent in grafts of both SPK and PTA recipients. In contrast to the pancreas, kidney allograft biopsies did not show any difference in the incidence of moderate/severe tubulointerstitial rejection for SPK and KTA recipients, 88% vs. 84% at 1 and 90% vs. 100% at 2 weeks (P = 0.52 at 1 and P-1.0 at 2 weeks). However, the incidence of a moderate/severe vascular rejection grade was significantly (P = 0.015) lower in SPK than KTA renal allografts (12% vs. 44%) at 1 week, but not at 2 weeks (11% vs. 12%; P = 1.0). Renal allograft survival in pigs is not affected by the addition of a pancreas from the same donor; indeed, vascular rejection at 1 week posttransplant was less severe in SPK than KTA recipients. The clinical and histological progression of pancreas allograft rejection is less severe in SPK than PTA recipients, consistent with clinical observations, suggesting that the kidney down-regulates or dilutes the immune attack against the pancreas. The results suggest that SPK does not predispose to more graft losses from irreversible rejection than KTA and also support the use of a more vigorous immunosuppressive regimen for PTA than SPK recipients in clinical practice.