We compared the effect of different immunosuppressive drug regimens on both mean and long-term allograft survival and the histologic appearance of donor/recipient chimeras in the ACI to Lewis rat heterotopic cardiac transplant model. Intraabdominal cardiac transplantation was performed in standard fashion and microchimerism was assessed using immunohistochemical staining of cut sections of recipient spleen and lymph nodes. All of the drug regimens studied resulted in excellent mean allograft survival. Furthermore, long-term (>120 day) allograft survival was consistently observed in each group. In fact, many of the recipients continue to have functioning heterotopic grafts even as they approach the end of the natural life span of a Lewis rat. Mixed allogeneic chimerism, however, was not observed with 100% frequency despite the consistent induction of graft tolerance. This finding may be related to the immunosuppressive agents used or the sensitivity of the immunohistochemical assay. Therefore, the exact role, if any, of chimerism in the induction of graft tolerance remains unanswered.