Earlier investigations have indicated a difference in the lipid profiles of drug-sensitive and drug-resistant tumor cells. This study was undertaken to evaluate the effect of alterations in the cellular lipid compositions by clofibrate (CPIB), an antihyperlipidemic agent, on mitoxantrone (Mtn) cytotoxicity in murine P388 leukemia cells sensitive (P388/S) and resistant (P388/Adr) to adriamycin and in human chronic myeloid leukemia (CML) cells. CPIB did not elicit any significant alterations in the lipid levels of P388/S cells, whereas in the P388/Adr cells it brought about a 14% and 49% decrease in the levels of cholesterol and triglyceride respectively. Inhibition of 3H-thymidine incorporation was utilized as a measure of cellular cytotoxicity. CPIB caused a dose dependent inhibition of DNA and RNA biosynthesis in P388/S, P388/Adr and CML cells. The combination of CPIB and Mtn induced a greater cytotoxicity in P388/Adr cells as compared to P388/S cells, as shown by enhanced inhibition of 3H-thymidine incorporation in P388/Adr cells. Similar results were observed when 3H-uridine was used as a measure of cellular cytotoxicity. These observations were further confirmed in fresh CML cell samples, in which the combination of CPIB with Mtn induced an irreversible and synergistic inhibition of DNA biosynthesis. Results warrant extensive studies on CPIB as a clinical modulator to enhance the antiproliferative activity of Mtn.