The graft-versus-leukemia (GVL) effect, mediated by donor T cells, has revolutionized the treatment of leukemia. However, effective GVL remains difficult to separate from graft-versus-host disease (GVHD), and many neoplasms are GVL resistant. Murine studies aimed at solving these problems have been limited by the use of leukemia cell lines with limited homology to human leukemias and by the absence of loss-of-function leukemia variants. To address these concerns, we developed a GVL model against murine chronic-phase chronic myelogenous leukemia (mCP-CML) induced with retrovirus expressing the bcr-abl fusion cDNA, the defining genetic abnormality of chronic-phase CML (CP-CML). By generating mCP-CML in gene-deficient mice, we have studied GVL T-cell effector mechanisms. mCP-CML expression of Fas or tumor necrosis factor (TNF) receptors is not required for CD8-mediated GVL. Strikingly, maximal CD4-mediated GVL requires cognate interactions between CD4 cells and mCP-CML cells as major histocompatibility complex-negative (MHC II(-/-)) mCP-CML is relatively GVL resistant. Nevertheless, a minority of CD4 recipients cleared MHC II(-/-) mCP-CML; thus, CD4 cells can also kill indirectly. CD4 GVL did not require target Fas expression. These results suggest that CPCML's GVL sensitivity may in part be explained by the minimal requirements for T-cell killing, and GVL-resistance may be related to MHC II expression.