BACKGROUND Many viruses have been engineered and evaluated for their potential as therapeutic agents in the treatment of malignant neoplasm, including malignant melanoma. OBJECTIVE In this study, we investigated the efficacy of HF10, an attenuated, replication-competent HSV, in immunocompetent animal models with malignant melanoma. METHODS For in vitro study, viral cytotoxicity assays and replication assays were performed both in human and mouse melanoma cells. For the study in vivo, intraperitoneally disseminated or subcutaneous melanoma models were prepared in DBA/2 mice using clone M3 cells, then HF10 was inoculated intraperitoneally or intratumorally. Therapeutic efficacy of HF10 was assessed by survival, tumor growth, and histopathological analysis. RESULTS HF10 infection produced cytolytic effects in melanoma cells at various multiplicities of infection (MOI). In the intraperitoneal melanoma model, all mice survived when given intraperitoneal injections of HF10 compared with 100% fatality in the control mice. In the subcutaneous tumor model, intratumoral inoculation of HF10 significantly reduced tumor growth. Histology and immunohistochemistry showed tumor lysis and inflammatory cell infiltration after intratumoral HF10 inoculation. Viral antigen was retained at the inoculation site until 7 days post-infection. HF10-treated intraperitoneal tumor mice were also protected against tumor rechallenge. HF10 also affected the non-inoculated contralateral tumor when injected into the ipsilateral tumor of mice, suggesting that HF10 can induce systemic antitumor immune responses in mice. CONCLUSIONS Oncolytic viral therapy using HF10 was effective in melanoma mouse models, and intratumoral injection of HF10 induced systemic antitumor responses. These results suggest that HF10 is a promising agent for the treatment of advanced melanoma.