Background: The immunomodulatory and immunosuppressive capacity of human mesenchymal stem cells (hMSC) is well recognized, but efficacies of hMSC in immunocompetent and immunocompromised animals have never been directly compared. Objectives: We aimed to compare the efficacy of hMSC in preventing bleomycin-induced lung injury in immunocompromised SCID and immunocompetent C57Bl/6 mice. Methods: SCID and C57Bl/6 mice were subjected to a single bolus intranasal instillation of bleomycin to induce lung injury. One million hMSC were administered intravenously 24 h following the induction of bleomycin lung injury. Results: hMSC xenotransplantation into SCID mice resulted in transient improvements in lung weight and tidal volume and to persistent improvement in inspiratory duty cycle, inspiratory flow rate and inspiration/expiration ratio. We did not observed protective effects in C57Bl/6 mice. This correlated with histological changes, where hMSC administration reduced Ashcroft scores, collagen deposition and inflammatory influx in the lungs of SCID mice, but not in those of C57Bl/6 mice. Conclusion: The application of hMSC for the treatment of acute and chronic lung injury is significantly affected by the immune status of the recipient. Lack of hMSC-mediated repair observed in C57Bl/6 mice was likely to be due to limitations of their immune privilege and differential priming of hMSC in immunocompetent versus immunocompromised hosts.