A vascularized heterograft model using outbred strains of animals was developed by transplanting mouse hearts heterotopically into rats. With this species desparity rapid but not immediate graft rejection was observed, with a predictably narrow range of graft survival times. Morphological and immunohistological studies showed early deposition of fibrinogen and vascular and myocardial inflammation without prominent or consistent localization of either IgG or C3. Later more extensive changes were observed, and deposition of IgG and C3 were more prominent in the grafts. Pretreatment of the recipient with cyclophosphamide alone or cyclophosphamide plus antigen prolonged graft survival; however, no statistically significant difference was noted between these groups. Morphological and immunohistological alterations preceded clinical rejection, and tissue injury appeared to be mediated by humoral and cellular immune mechanisms and by the coagulation system. This model is potentially useful for the study of heterotransplantation.