The effects of exposure of normal and Rauscher leukemic mice to a combination of the chemotherapeutic drug, piperazinedione, plus total-body irradiation (TBI) were evaluated. Three different protocols of piperazinedione given in two doses prior to TBI significantly reduced survival of endogenous CFU-S in the spleens of leukemic mice compared to TBI alone. Similar results were obtained in two of the three protocols when applied to normal mice. Piperazinedione given to leukemic mice on the same day as TBI resulted in a large number of early deaths. Evaluation of the effects of all three protocols on the intestinal crypts and villi of leukemic mice showed a significant effect on the intestine when drug and TBI were given on the same day, but negligible effects when the drug was given several days prior to TBI. Evaluation of survival curves of leukemic mice given marrow transplantation following piperazindedione plus TBI showed that survival could be significantly improved over that obtained using TBI alone when the drug was given 6 and 5 days prior to TBI and transplantation. The results suggest that the drug may be an effective ablative agent for marrow-transplantation therapy of leukemia.