Arsenic Trioxide (ATO) has been shown to be highly active against acute promyelocytic leukemia (APL) and has activity in several other diseases including multiple myeloma. While initial clinical trials in both APL and myeloma have suggested that melarsoprol results in greater dose-limiting toxicities than ATO, it is generally accepted that organic arsenicals are less toxic than inorganic arsenicals. Consequently, organic arsenicals that kill myeloma cells could be clinically more effective than ATO. Recently, several organic arsenicals were synthesized that have EC50s similar to ATO against cell line panels but are > 10-fold less toxic. One such compound, ZIO-101 is in phase I studies. Therefore we compared the ability of ZIO-101 and ATO to kill four myeloma cell lines that display differential sensitivity to ATO. The RPMI 8226 and U266 are less sensitive than the KMS11 and MM.1s lines. When dose response curves were generated comparing ATO and ZIO-101 at 24, 48 and 72 hrs we found that the U266, KMS11 and MM.1s lines were consistently 1–3 fold less sensitive to ZIO-101 than to ATO. However if one considers the number of atoms of elemental arsenic/molecule of drug, these data would suggest that the ability of these drugs to kill MM cell lines is similar. In contrast the 8226 line was more sensitive to ZIO-101. Additionally we have previously reported that ATO induces caspase-dependent and -independent cell death in a cell specific fashion in these lines. We found a similar pattern of caspase dependence with ZIO-101 where BocD-FMK, a caspase inhibitor, completely blocks ZIO-101-induced killing of U266, partially blocks killing of MM.1s and KMS11 and has no effect no killing of 8226. These data suggest that the downstream components of the death signaling pathway induced by ZIO-101 and ATO are similar. In contrast, initial responses to these drugs differ. We and others have reported that glutathione (GSH) is a critical regulator of ATO-induced cell death and have utilized ascorbic acid (AA) as a GSH depleting agent both in vitro as well as clinically. We therefore tested the effects of GSH depletion on ZIO-101 induced cell death in MM cell lines. Using concentrations of ATO and ZIO-101 that had similar activity, we determined the effects of both an inhibitor of GSH synthesis (BSO) as well as AA that can transient deplete GSH. BSO sensitized all 4 cell lines to both agents, however it was much more effective at sensitizing cells to ATO than to ZIO-101. Moreover while AA could sensitize cells to ATO, it actually protected cells from cell death induced by ZIO-101. Taken together these data suggest that ZIO-101 has activity against myeloma cells although factors that determine the potency of this compound are different than those for ATO. This may reflect differences in either metabolism or mechanism of action. Thus resistance to one form of arsenic does not preclude the use of another. A phase I/II study of ZIO-101 in myeloma is planned.