The purpose of this study was to establish a model and to define the mechanism of rejection for the transplantation of vascularized musculoskeletal xenografts between C57BL/6j (B6) mice and Lewis rats. This was accomplished by using conventional skin xenografts to determine immunologic baseline data between these species and by performing musculoskeletal grafts from the B6 mice transplanted into Lewis rats. After the transplant, the xenografts were examined histologically and the recipients were assessed for immune reaction using in vitro assays to measure both cell-mediated and humoral responses. The results obtained from the skin xenografts showed activation of both cellular and humoral immunologic responses. All musculoskeletal xenografts were rejected between 3 and 4 postoperative days. Histologically, the grafts showed extensive vascular injury manifested by thrombosis and hemorrhage, suggesting an early humoral response. Anti-donor antibody production was detected in the recipient's sera soon after rejection of the xenogeneic tissue. The cell-mediated immune response, although detectable by the in vitro assays, was less pronounced than the humoral response and corroborated the histologic findings of mild lymphocyte infiltration in the rejected tissue. These results demonstrate that humoral rejection plays a predominant role in the rejection of vascularized musculoskeletal xenotransplants between concordant species. This mouse-to-rat vascularized xenograft model will be utilized for further studies on inducing tolerance to vascularized musculoskeletal xenografts.