B-lymphoma cells express a highly tumor-specific antigen, monoclonal Ig, which is a promising target for immunotherapy. Previous work has demonstrated that B-lymphoma cells spontaneously process their endogenous monoclonal Ig and present variable (V) region peptides (Id-peptides) on their MHC class II molecules to CD4+ T cells. Id-specific CD4+ T cells protect mice against B-lymphoma cells in the absence of antiidiotypic antibodies. The molecular mechanism by which Id-specific CD4+ T cells kill B-lymphoma cells is hitherto unknown. We here demonstrate in an Id-specific T-cell receptor (TCR)-transgenic mouse model that Id-specific CD4+ T cells induce apoptosis of Fas+ B-lymphoma cells in vitro by FasLigand (FasL)-Fas interaction. Moreover, the rare B lymphomas that had escaped rejection in TCR-transgenic mice had down-regulated their sensitivity to Fas-mediated apoptosis. Although these results suggest that FasL-Fas interaction is important, Id-specific CD4+ T cells could eliminate Id+ B-lymphoma cells in vivo by other mechanisms, since three independent ways of blocking FasL-Fas-mediated killing failed to abrogate tumor protection in TCR-transgenic mice. These results suggest that there are several redundant pathways by which Id-specific CD4+ T cells eliminate Id+ B-lymphoma cells in vivo, of which FasL-Fas interaction is only one.