Vaccination of mouse myeloma V(K)C(K)-gamma (I) cells secreting interferon (IFN)-gamma and expressing enhanced major histocompatibility complex (MHC) class I antigen (Ag) resulted in protective immunity that was mainly mediated by CD8+ T cells. V(K)C(K)-gamma (I/II) cells expressing both enhanced MHC class I and class II Ags were isolated from V(K)C(K)-gamma (I) cells. These V(K)C(K)-gamma (I/II) cells were used to study the relationship between IFN-gamma secretion of tumor cells, its tumorigenicity, and its induced immunity, as well as to evaluate the cellular immunocomponents mediating this immunity. Our animal studies showed that IFN-gamma secretion by V(K)C(K)-gamma (I/II) cells curtailed its tumorigenicity in syngeneic BALB/c mice and further induced protective immunity against a subsequent graft of parental V(K)C(K) tumor. This immunity is mediated by both CD4+ and CD8+ T cells. The activation of CD4+ T cells is associated with enhanced expression of MHC class II Ag of V(K)C(K)-gamma (I/II) cells. These CD4+ T cells are tumor specific and cytolytic in an MHC-restricted fashion in vitro, and are tumoricidal in a T-cell adoptive transfer experiment in vivo. Our data thus demonstrate that vaccination of genetically modified tumor cells secreting IFN-gamma may provide beneficial antitumor effects by inducing both cytolytic CD4+ and CD8+ cytotoxic T lymphocytes, provided that these tumor cells express both enhanced MHC class I and class II Ags.