Inorganic arsenic trioxide (As 2 O 3) is a highly effective treatment for acute promyelocytic leukemia (APL). However, other cancers do not respond well to this form of arsenic at clinically achievable doses. We tested a novel arsenical, S-dimethylarsino-glutathione (darinaparsin) for efficacy in various malignancies in vitro. Darinaparsin is significantly more potent than As 2 O 3 at mediating apoptosis in various malignant cell lines and is highly active against APL cells derived for As 2 O 3 resistance. We provide evidence that darinaparsin triggers apoptosis by inducing signaling pathways that do not completely overlap with As 2 O 3. We show that darinaparsin induces apoptosis and oxidative stress to a greater extent than As 2 O 3, although like As 2 O 3, darinaparsin-induced toxicity is c-Jun NH 2-terminal kinase-dependent. However, darinaparsin does not induce promyelocytic leukemia/retinoic acid receptor α (PML/RARα) degradation or rearrange PML nuclear bodies in APL cells, nor is its toxicity increased by glutathione depletion. Darinaparsin treatment results in higher intracellular arsenic accumulation when compared to As 2 O 3 treatment. This may be explained by our finding that As 2 O 3, but not darinaparsin, is efficiently exported by ABCC1, suggesting increased therapeutic efficacy of darinaparsin in ABCC1-overexpressing tumors. Our studies indicate that darinaparsin efficiently kills tumor cells with increased antioxidant capacity and drug exporters and suggest that darinaparsin may have a broader therapeutic spectrum than As 2 O 3.