The role of major histocompatibility (MHC) versus non-MHC determinants in the antileukemic effect exerted by engrafted normal marrow (graft-vs-leukemia, GvL) was studied in Rauscher leukemic SJL/J mice. The marrow donor strains included normal syngeneic SJL/ J (H-28), allogeneic C57BL/10 and 129/J (H-2b), congenic B10.S (H-28, but otherwise genetically identical to the C57BL/10), and also F1 hybrid mice of the SJL/J and B10.S or C57BL/10 strains. Prior to transplant the recipients were exposed to a dose of total body irradiation that was large, but lower than that required to eliminate all hematopoietic precursors, such that GvL activity of the donor marrow would be necessary to avoid leukemic relapse. Total relapse within 60 days was observed when the syngeneic SJL/J donors were used. Transplantation either of the H-2b C57BL/10 or the H-2b B10.S marrow resulted in approximately 50% unrelapsed survival at 4 months. In contrast, only 26% unrelapsed survival was obtained with H-2b 129/J marrow. Marrow from (SJL/J × B10.S)F1 hybrids yielded a survival curve that was intermediate between those for the two parental strains; a similar but somewhat improved pattern was seen with (SJL/J × C57BL/10)F1-hybrid donors. The results suggest that although MHC genetic differences between the donor and recipient may produce a GvL effect in marrow transplantation therapy, other non-MHC determinants may also be capable of exerting an independent GvL effect of at least equivalent strength. © 1983 by The Williams and Wilkins Co.