Many cancers can cause disability and pain by invading nerves. In particular, prostate carcinoma has a high propensity for neural invasion (NI) at an early stage. Attempted surgical treatment of tumors with NI often leads to erectile dysfunction and deteriorated quality of life. Therefore, there is a need for novel modalities that will selectively target cancer cells while preserving neural function. Herpes simplex viruses (HSVs) have a natural trophism for peripheral nerves. We hypothesized that oncolytic therapy using HSV engineered to minimize neurotoxicity would be appropriate for this clinical setting. Attenuated HSV (NV1023) injected to sciatic nerves of nude mice had no toxic effect on nerve function (n=30). NV1023 had significant oncolytic effect on prostate carcinoma cells (PC3, DU145, and LNCap) in vitro. An in vivo model of NI was established by implanting prostate carcinoma cells in the sciatic nerves of nude mice. Mice were treated with NV1023 or saline 7 days after establishment of tumors. Significant reduction in tumor size and inhibition of NI was found 6–8 wk after treatment (P<0.005). All animals treated with saline developed complete paralysis <5 wk post-treatment, whereas most NV1023-treated animals had preserved nerve function >12 wk after treatment (P<0.0001). We conclude that oncolytic therapy effectively treats prostate carcinomas with NI in an in vivo murine model while preserving neural function. These findings may hold significant clinical implications for patients with prostate cancer or other neurotrophic tumors.—Kelly, K., Brader, P., Rein, A., Shah, J. P., Wong, R. J., Fong, Y., Gil, Z.—Attenuated multimutated herpes simplex virus-1 effectively treats prostate carcinomas with neural invasion while preserving nerve function.