Xenotropic murine leukemia virus-related virus (XMRV) resembles endogenous murine leukemia virus and was used in this study as a model for a new retrovirus infecting human cells. We demonstrate that induction of an HO-1-mediated host cell response inhibited the susceptibility of LNCaP prostate cancer cells to XMRV infection and efficiently retarded the growth of these prostate cancer cells. Our studies delineate a role of HO-1 in the host defense against retroviral infections and may provide novel therapeutic strategies for the treatment of HO-1-sensitive prostate cancer.