Inadequate vascularization and microvascular rejection are major limitations for successful free pancreatic islet xenotransplantation. Commonly used immunosuppressive regimens may alter the process of vascularization, and are ineffective at preventing graft rejection. In this study, we investigated, in vivo, the action of the new immunosuppressive agent RS-61443 on angiogenesis and microvascular rejection of rat pancreatic islets after xenogeneic transplantation into the dorsal skinfold of Syrian golden hamsters. In nontreated xenografts, intravital fluorescence microscopy demonstrated a regular process of vascularization during the first 6 days after transplantation. On days 10, 14, and 20, graft rejection was observed, characterized by microvascular leukocyte accumulation (244+/-59 mm(-2)), loss of endothelial integrity, and capillary perfusion failure. Islet xenografts of animals treated with RS-61443 (40 mg/kg per day) demonstrated inhibition of vascularization with the consequence of a markedly reduced size of the grafts' microvascular network (0.05+/-0.007 mm2), when compared with that of nontreated xenografts (0.09+/-0.015 mm2; P< 0.05). However, treatment with RS-61443 effectively prevented microvascular graft rejection, as indicated by the absence of leukocyte accumulation (24+/-9 mm(-2); P<0.01), endothelial damage, and nutritive perfusion failure. Thus, RS-61443 treatment may represent an interesting approach for improving the outcome of pancreatic islet xenotransplantation.