Fusogenic membrane glycoproteins (FMG) are a family of viral genes that, when expressed in tumour cells, trigger extensive cell to cell fusion and subsequent cell death. Gene therapy approaches using FMG are also potentially immunogenic, since syncitia generated ex vivo can be therapeutic as antitumour vaccines in murine models. This study has addressed the mechanisms responsible for the immunogenicity of FMG-mediated cell death, and its applicability to human immune priming. We show that fusion of human Mel888 melanoma cells following transfection with FMG can reverse the suppressive effects of Mel888 on dendritic cells (DC) phenotype, and potentiate IL-12 production by DC on activation in a cell contact-dependent manner. DC loaded with fusing, but not intact, tumour cells primed a naive, tumour-specific cytotoxic T-cell response, which was MHC class I-restricted and associated with production of high levels of IFNgamma and, later, IL-5. Fusing cells were an effective source of antigen for DC cross-priming and presentation of the melanoma-specific antigen gp100 to a specific T-cell clone. These data show, in a human system, that FMG represent an immunogenic, as well as cytotoxic, gene therapy for cancer, reversing the inhibitory effects of tumour cells on DC to potentiate IL-12 production and naive T-cell priming.