Anthracyclines are active against a variety of malignancies. The present study examined the effect of epirubicin and idarubicin on in vitro polymorphonuclear (PMN) function including chemotaxis, aggregation, bacteriocidal activity degranulation, and superoxide generation. We also studied the effects of cyclosporin (100 ng/ml) and verapamil (500 ng/ml), two membrane active biological response modifiers, on their potential role in modulating anthracycline-induced oxygen radical formation in the human PMN. Older anthracyclines (doxorubicin and daunorubicin) did not affect superoxide generation in the human PMN. However, the newer anthracyclines, both epirubicin and idarubicin, profoundly inhibited human superoxide generation (P less than .02) and (P less than .01), respectively. This inhibition was not agonist specific but occurred with multiple agonists including FMLP, PMA, A23187, and Zymosan-activated serum (ZAS). Last, cyclosporin and verapamil did not modulate the anthracycline effects of PMN superoxide generation. This study suggests that two of the newest anthracyclines, epirubicin and idarubicin, inhibit more PMN superoxide radical formation compared to their parent compounds. This reduction in oxyradical formation may account in part for their difference in anthracycline cellular cytotoxic activity.