Schedule dependency of idarubicin (Ida) and doxorubicin (Dox) toxicity was investigated in vitro using the K562 human leukemia cell line. For Dox, repeated exposure to the IC30 (d x 3) resulted in comparable survival as single exposure to the total accumulative dose (20%). For Ida, repeated exposure to the IC30 (d x 3) decreased survival to 5%, while single exposure to the total accumulative dose reduced survival only to 20%. Total cellular accumulation of Dox was independent of schedule of exposure, while for Ida, repeated exposure resulted in a significantly higher drug accumulation compared to the single exposure to the accumulative dose. The data indicate that the schedule-dependent differences in cytotoxicity for the two compounds can be accounted for almost exclusively by an increased cellular uptake and retention of Ida with repeated drug exposure.