Inactivated Sendai virus particles (hemagglutinating virus of Japan envelope; HVJ-E) are considered to be safe and efficient non-viral vectors used for drug delivery, since they can incorporate DNA, RNA, proteins and drugs. We have recently found that HVJ-E has a novel antitumor immune effect using a colon cancer model. HVJ-E has also been shown to have both direct and immune-mediated indirect actions against malignancy. Intratumoral injection of an inactivated HVJ-E solution significantly reduced the tumor volume and prevented spontaneous lung metastasis, leading to an increased overall survival in C57/BL6 mice transplanted with B16/BL6 mouse melanoma cells, and even in immunodeficient mice transplanted with Mewo human melanoma cells. No severe adverse effects including laboratory data abnormalities or anaphylactic reactions were observed. The comprehensive mechanism(s) underlying the immunological effects of HVJ-E appear to include not only enhanced effector T cell- and/or natural killer (NK) cell-mediated immunity, but also rescue from regulatory T cell (Treg)-mediated immunosuppression, presumably through the interleukin-6 secretion from dendritic cells stimulated by HVJ-E. Since a protocol for a clinical study of HVJ-E in malignant melanoma was approved in 2009 by the ethics committee of Osaka University and of the Medical Center for Translational Research in Osaka University Hospital, a phase I/IIa study for advanced malignant melanoma patients was just started. In this review, we show several favorable results regarding the antitumor effects of HVJ-E and describe the novel mechanism underlying this tumor immune response. Since we are conducting a phase I/IIa clinical trial using HVJ-E in advanced melanoma patients on the basis of preclinical results, detailed clinical information and immune-monitoring data are also introduced. The development of new therapeutic modalities for advanced melanoma patients is urgently needed, and we hope that HVJ-E may provide one such treatment.