The effects of the anti-allergic drug azelastine on the P388 murine leukemia cell line (P388) and the K562 human leukemia cell line (K562) and their adriamycin (ADM)-resistant sublines P388/ADM and K562/ADM were examined with respect to the cytotoxic effect, cellular accumulation and retention of ADM. Azelastine enhanced the cytotoxicity of ADM toward P388 and K562 cells slightly but toward P388/ADM and K562/ADM cells greatly. Azelastine was found to increase the intracellular levels of ADM in both P388/ADM and K562/ADM cells by inhibiting the outward transport of the drug. The high intracellular accumulation of ADM accounts for the enhancement of the cytotoxicity of ADM, and thus the ADM-resistance of these cells was partially circumvented.