Cytotoxic effect in vitro and antitumor effect in vivo of doxorubicin (DOX) combined with cepharanthine were investigated on DOX-resistant murine P388 leukemia (P388/R) cells. Cepharanthine was minimally cytotoxic in the cell line, but reversed DOX-resistance in a dose-related manner in P388/R cells. The administration of cepharanthine to mice bearing the P388 leukemia enhanced the antitumor activity of DOX. These results indicate that cepharanthine is an effective agent to reverse DOX-resistant cells.