The clinical efficacy of arsenic(III) oxide (As(2)O(3)) has been shown in patients with relapsed acute promyelocytic leukemia (APL). To identify potential common primary targets of action of As(2)O(3) in myelogenic and lymphatic cell lines, we analyzed As(2)O(3) effects on caspases and on the mitochondrial membrane potential (Psi(M)) under uniform conditions. As(2)O(3) induced breakdown of Psi(M) and activated caspases in cell lines with different sensitivities for As(2)O(3), including cell lines resistant to mitoxantron or camptothecin but sensitive to As(2)O(3). Caspase inhibitors could not prevent breakdown of Psi(M) in lymphoid cell lines, whereas activation of caspases and apoptosis could be inhibited. Activation of caspases seems to be a downstream effect occurring after breakdown of Psi(M). We could show that all of these effects are independent of MDR-1 expression. There was no difference in the mode of action of As(2)O(3) in cell lines sensitive or resistant to camptothecin, mitoxantrone, or doxorubicin. As(2)O(3) deserves further evaluation as an adjunct or alternative to other cytostatic drugs.