Adult stem cells represent a potential source for cell-based therapy of cancer. The present study evaluated the potential of bone marrow-derived mesenchymal stem cells (MSC), genetically modified to express interferon (IFN)-α, for the treatment of lung metastasis in an immunocompetent mouse model of metastatic melanoma. A recombinant adeno-associated virus (rAAV) 6 vector encoding IFN-α was used to transduce mouse bone marrow-derived MSC ex vivo. Expression and bioactivity of the transgenic protein from rAAV-transduced MSC were confirmed prior to in vivo studies. A lung metastasis model of melanoma was developed by i.v. injection of B16F10 cells into 8-week-old C57BL/6 mice. Ten days later, MSC transduced with rAAV-IFN-α or green fluorescent protein were intravenously injected. One cohort of mice was sacrificed to determine the effects of the therapy at an earlier time point, and another cohort was observed for long-term survival. Results indicated that systemic administration of MSC producing IFN-α reduced the growth of B16F10 melanoma cells and significantly prolonged survival. Immunohistochemistry analysis of the tumors from MSC-IFN-α-treated animals indicated an increase in apoptosis and a decrease in proliferation and blood vasculature. These data demonstrate the potential of adult MSC constitutively producing IFN-α to reduce the growth of lung metastasis in melanoma. ©AlphaMed Press.