Viral gene therapy against malignant tumors holds great promise for tumors that are susceptible to the oncolytic activity of viruses. One advantage of oncolytic viral therapy is that it can potentially be combined with other therapies, such as radiotherapy, to obtain an enhanced tumor response. In the case of prostate cancer, herpes simplex virus-mediated therapies have been shown to be highly effective in animal models; however, studies of the efficacy of combined viral and radiation therapy have not yet been reported. In this study, we have combined G207, a multimutated HSV type 1 vector, with external beam radiation therapy of prostate tumors grown subcutaneously in mice. We examined both the human LNCaP tumor in athymic mice and the mouse transgenic TRAMP tumor in either athymic mice or its syngeneic host, C57BL/6 mice. Virus was delivered either intravenously, in the case of LNCaP, or intratumorally, in the case of TRAMP. We found that individually, either G207 or radiation was effective in delaying tumor growth in these models. However, delivering the treatments simultaneously did not produce an enhanced effect.