The origins of "help" in rejection of syngeneic tumors by the CD8 T cell lineage was examined with a model tumor inappropriately expressing novel class I MHC and subject to cytolytic T cell (CTL)-mediated rejection. The requirement for CD4+ Th cells to induce CD8+ CTL effectors in vivo was investigated by using C3H mice selectively depleted of either CD4+ or CD8+ T cells. Rejection of the tumor was vigorous and indistinguishable from normal mice after depletion of CD4+ T cells in vivo. In contrast, in CD8+ T cell-depleted mice tumors grew progressively, confirming that T cells of the CD8+ lineage are required for a tumoricidal immune response, and cells of this lineage are sufficient for a primary response. Taken together, these results demonstrate that, in the absence of CD4+ T cells in vivo, unprimed cells of the CD8+ lineage are fully competent to mount an effective CTL immune response to syngeneic cells expressing novel class I Ag, consistent with the concept that only T cells with class I recognition specificity may be required to satisfy the need for both help and effector functions in the response.