Background: Xenogeneic hematopoietic engraftment holds promise as a strategy to achieve whole organ xenograft tolerance. We tested whether xenogeneic bone marrow grafts, engineered with mesenchymal stem cells (MSCs), might provide a new nontoxic approach to enhance xenogeneic engraftment. Methods: ACI rat MSCs, cultured from whole bone marrow, were identified as CD29+ CD44+OX-18+, CD45-HIS36- and could differentiate into adipogenic and osteogenic tissue. Lethally irradiated B6 mice received ACI whole bone marrow either alone or in combination with ACI MSC. Xenogeneic engraftment was measured in murine peripheral blood on days 7, 50, and 100. Natural killer (NK)-cell-depleted murine recipients treated with or without MSC underwent rat skin graft transplants on the day of the bone marrow infusion. Results: In NK-depleted hosts, control animals failed to survive 60 days; 40% MSC-treated hosts survived >100 days, P < 0 .05. Rat hematopoietic engraftment exceeded 89% on days 7 and 54 and decreased to <25% by day 100. No graft-versus-host disease was observed in MSC-treated animals, P < 0.05. Skin graft survival was prolonged in the MSC-treated group, (21 ± 1.7 days, P = 0.2). Conclusions: Our findings present a new approach in engineering xenografts and provide an encouraging platform for additional studies.