(A/J x C3H/HeJ)F1 mice (H-2a/k) exhibit no apparent resistance to the malignant proliferation of ASL-1 leukemia cells (H-2a), a spontaneously occurring neoplasm of A/J mouse origin. The period of survival after injections of ASL-1 cells is related to the number of cells introduced into the susceptible host. (A/J x C3H/HeJ)F1 mice receiving viable ASL-1 cells along with ASL-1 x LM(TK)- somatic hybrid cells (H-2a/k), syngeneic with the recipients, survived for statistically significant (p less than 0.001), longer periods than did mice receiving ASL-1 cells alone. Mice receiving ASL-1 and ASL-1 x LM(TK)- hybrid cells together survived for approximately twice as long as animals receiving ASL-1 cells alone. Mice receiving ASL-1 cells followed by hybrid cells survived for longer periods as well, but the therapeutic effects were less successful. ASL-1 x LM(TK)- hybrid cells are rejected after forming localized tumors by the immunocompetent F1 mice. In some instances, F1 animals previously rejecting hybrid cells and challenged subsequently with ASL-1 cells along with a second injection of hybrid cells survived indefinitely. The passive transfer of partial immunity to the leukemic cells could be achieved by injections of spleen cells from F1 mice that had rejected hybrid cells previously. Similar results were obtained for (A/J x C3H/HeJ)F1 mice receiving RADA-1 cells (H-2a), a radiation-induced leukemic line of A/J origin, along with RADA-1 x LM(TK)- hybrid cells (H-2a/k). The partial immunity induced by these lines of hybrid cells was cross-reactive: mice injected with ASL-1 cells and RADA-1 x LM(TK)- hybrid cells survived for prolonged periods, and vice versa.