Acquired resistance to doxorubicin in a P388 murine leukemia cell subline was found to be associated with decreased drug accumulation in these cells. We have previously shown that the lipid domain of the plasma membrane in drug-resistant cells is structurally more ordered and has a lower phosphatidylcholine/sphingomyelin ratio. Perhexiline maleate and triparanol both markedly enhance the sensitivity of drug-resistant cells to doxorubicin and vinblastine but do not have an effect on anthracycline-sensitive cells. This enhanced sensitivity is associated with increased drug accumulation. Although perhexiline maleate has been reported to be a calcium antagonist in other systems, our data do not implicate this mechanism in the enhancement of cell sensitivity to doxorubicin. We suggest that this effect might be related to alterations of the cell membrane lipid domain induced by perhexiline maleate and triparanol, which result in decreased structural order of plasma membrane lipids and permit increased drug accumulation.