Donor-derived antigen-presenting cells (APC) are thought to serve as major stimulators for triggering the rejection of tissue allografts. However, the capacity of APC to stimulate xenogeneic T cells is generally deficient relative to the corresponding response from allogeneic T cells. For this reason, the contribution of donor-type APC to xenogeneic graft rejection remains unclear. Using a concordant species combination (rat to mouse), we examined the requirement for donor-type APC in triggering islet xenograft rejection. While the depletion of donor-type APC resulted in indefinite allograft survival, similar depletion of APC from xenogeneic rat islets resulted in only modest graft prolongation. Furthermore, APC-depleted rat xenografts were rejected by a CD8+ T cell-independent mechanism, as determined by appropriate depletion of T cell subsets through monoclonal antibody therapy. This contrasts with the dependence of islet allograft rejection on both CD4+ and CD8+ T cells. Although in vitro experiments show that rat APC can directly stimulate mouse T cells, rat APC do not appear to be required for xenograft immunity in vivo. We conclude that the mechanisms of islet allograft and xenograft rejection differ both in the dependence on donor-type APC and in the role of T cell subsets in the response.