The aim of this study was to investigate the combined effect of DLA matching and immunosuppressive therapy on the survival of segmental small-bowel allografts in dogs. Orthotopic segmental small-bowel transplantations (25 to 30% of total small bowel length) were performed in two stages: first a heterotopic segmental small bowel transplantation, followed after 5 to 8 weeks by a second-stage operation during which the heterotopic graft was placed in an orthotopic position and the native small bowel was resected. All dogs received cyclosporine immunosuppression. Control dogs (n = 4), subjected to total enterectomy, survived 37.3 +/- 7.1 days (mean +/- SEM). Recipients of DLA-mismatched small bowel grafts (n = 6) survived 113.2 +/- 37.0 days, which was a significantly shorter time than dogs with a DLA-matched graft (n = 6, 211.5 +/- 38.8 days, P < 0.05). None of the matched allografts was rejected during CsA treatment, whereas four of six mismatched grafts were (P < 0.05). The control dogs uniformly showed progressive weight loss, steatorrhea, and hypoalbuminemia. The dogs with DLA-mismatched grafts did not regain initial body weight, whereas animals with DLA-matched grafts recovered preoperative weight after 20 weeks. Both transplanted groups showed near-normal fecal fat excretions and constant serum albumin, cholesterol, and triglyceride levels, whereas serum total protein levels increased during follow-up. We conclude that segmental small bowel transplantation between DLA-matched donor-recipient pairs results in long-term survivors with an adequate nutritional status. This may have important implications for future living-related small-bowel transplantation.