We propose that one manifestation of altered sphingolipid metabolism within tumor cells may be a reduced sensitivity to anti-cancer therapies because of an inability to produce a sufficient apoptotic signal via sphingomyelin hydrolysis to ceramide, If so, then sphingomyelin administration could reverse this effect and increase a tumor's sensitivity to chemotherapy, In vivo intravenous sphingomyelin (10 mg/day, 7 days) potentiated B-fluorouracil chemotherapy (0.45 mg/day, 5 days) when co-administered to HT29 human colonic xenograft-bearing nude mice. In vitro, sphingomyelin (SM) at its maximum tolerated concentration increased 5-fluorouracil and doxorubicin sensitivity of HCT15 and MOSER (1 mg/ml SM.) and LS174T and SW480 human colonic tumor cells (0.1 mg/ml) approximately 100-300%. At I mg/ml SM, however, no effect was seen using HT29, LoVo and WiDr cells. There was no sensitization of normal human umbilical cord endothelial cells. Thus, sphingomyelin coadministration may be one method to improve the selective efficacy of chemotherapy in some tumors, possibly through enhancement of the apoptotic response.