Human mesenchymal stem cells (hMSCs) have been used to improve engraftment and to treat graft versus host disease following allogeneic hematopoietic stem cell transplantation. However, oxidative stress presented in the microenvironment can damage the transplanted hMSCs and therefore reduce their survival in target organs. We investigated how to enhance the survival of hMSCs under oxidative stress by overexpressing secreted frizzled-related protein 2 (sFRP2) gene in bone marrow-derived hMSCs and umbilical cord-derived hMSCs. The survival and characteristics of those sFRP2-overexpressing hMSCs (sFRP2-BM-hMSCs and sFRP2-UC-hMSCs) were studied compared with non-transduced hMSCs. We found that the percentages of viable cells in culture of sFRP2-BM-hMSCs and sFRP2-UC-hMSCs in the absence or presence of 0.75 mM H2O2 were significantly higher than those of their non-transduced counterparts. The overexpression of sFRP2 gene did not affect the characteristics of hMSCs regarding their morphology, surface marker expression, and differentiation potential. Our study suggests that overexpression of sFRP2 gene in hMSCs might improve the therapeutic effectiveness of hMSC transplantation.