Previously, we reported that transplantation of rat bone marrow into lethally irradiated (950 rads) mouse recipients results in stable xenogeneic (rat-->mouse) chimerism and confers donor-specific transplantation tolerance for subsequent or simultaneous islet xenografts. For potential clinical application of chimerism to induce tolerance, it would be important to avoid the morbidity and mortality associated with lethal conditioning. Recently, we established a model to achieve durable multilineage xenogeneic chimerism using a nonlethal cytoreductive approach. We report here for the first time that donor-specific rat islet xenografts placed coincident with the bone marrow transplant are permanently accepted by nonlethally conditioned recipients. All recipients conditioned with 700 cGy of total body irradiation and transplanted with 40 x 10(6) F344 rat bone marrow cells repopulated as mixed donor/host chimeras. The chimeras exhibited permanent acceptance of donor islet xenografts, since donor-specific F344 (Rt1A1) rat islet xenografts were significantly prolonged (median survival time > 110 days), while MHC-disparate third-party WF (Rt1Au) rat islets were prolonged but rejected (median survival time = 33.2 days). The islets were functional to maintain normoglycemia and regulated in function to respond to an intraperitoneal glucose challenge. These data suggest that tolerance to donor-specific islet xenografts placed coincident with bone marrow transplantation can be achieved after nonlethal conditioning.