We examined the therapeutic effect of lipopolysaccharide (LPS), a differentiation inducer, in combination with daunomycin, an antileukemia drug possessing differentiation-inducing potential, on a rat myelomonocytic leukemia (c-WRT-7). c-WRT-7 cells were found to differentiate into macrophage-like cells and to lose their growth capacity both in vitro and in vivo after incubation with LPS. Morphological differentiation of c-WRT-7 cells was observed in diffusion chambers which had been inserted into the abdominal cavity of syngeneic WKA rats given injections of LPS. A series of i.p. injections of LPS resulted in the complete inhibition of the leukemia development in about 60% of the rats while the remaining rats showed a significant prolongation of survival time when they were given i.p. injections of LPS-sensitive c-WRT-7 cells. The effect of LPS was minimal, however, in those rats which had been given i.p. injections of LPS-hyporesponsive c-WRT-7 cells. Although an i.v. injection of 100 untreated c-WRT-7 cells was enough to kill the syngeneic rats, combination treatment with LPS and daunomycin was able to inhibit completely the development of leukemia in those rats which had been given i.v. injections of LPS-sensitive c-WRT-7 cells, whereas the same treatments were only partially effective in the prolongation of survival among those rats which had been given i.v. injections of LPS-hyporesponsive c-WRT-7 cells. Our studies show that LPS was capable of curing a proportion of rats and that it significantly prolonged the survival of the remainder who had received a transplantation of the differentiation-sensitive leukemia cells; this action was significantly enhanced by the associated administration of daunomycin.