A membrane stabilizer, the biscoclaurine alkaloid cepharanthine markedly enhanced the cytotoxicity of vincristine (VCR) and adriamycin in cultured L1210 cells at a noncytotoxic dose. When 0.1-0.5 micrograms cepharanthine/ml was added along with VCR to L1210 cells in vitro, the cytotoxicity of VCR was potentiated 1.5-fold to 7-fold, whereas such potentiation was not found in mitomycin C, bleomycin, and 5-fluorouracil. The potentiating action of cepharanthine was stronger when the cells were preincubated with cepharanthine prior to the treatment of cells with VCR and cepharanthine, suggesting that a long-term contact with cells is required for the enhancement. Cepharanthine was found to induce the increase of the cellular level of VCR in L1210 cultured cells. It was suggested that the accumulation of VCR is due to the inhibition of a VCR efflux function of the cells. The administration of cepharanthine at the dose of 5 mg/kg/day for 10 days with VCR significantly enhanced the antitumor activity of VCR in L1210 leukemia and P388 leukemia (P less than .025). However, the combined effect of cepharanthine and VCR in this regimen was marginal synergism. When the same dose of cepharanthine was administered in split administration, three times daily for 10 days, the therapeutic effect of VCR was further enhanced compared to its effect under the former regimen. Furthermore, cepharanthine was found to partially overcome the resistance of VCR in P388/VCR.