We previously showed that arsenic trioxide (ATO) and melarsoprol may inhibit the growth of multiple myeloma (MM) cells in vitro and in vivo. We report here the administration of arsenic derivatives in 12 relapsing or refractory secretory MM patients. A total of 10 patients received ATO (eight in a continuous schedule, two discontinuously) and two received melarsoprol. The melarsoprol arm was prematurely closed due to toxicity. In the ATO arm, median duration of treatment was 38 days (9–54). Hepatic toxicity was grade 3 and 2 in one and eight patients, respectively. Other toxicities included neuropathy (n= 2, grade 2), encephalitis (n= 1, grade 3) and leuconeutropenia (n= 4, grade 3). At 2 weeks after treatment initiation, mean serum concentration of arsenic was 1.11±0.16 μmol/l. No complete or partial remission was observed. A minor response (25–49% reduction of M protein in serum) and a stabilization of the M-protein level were observed in three and four patients, respectively. After ATO discontinuation, these responses were of short duration in all cases. ATO as a single agent did not produce any significant response in advanced MM patients despite sufficient arsenic exposure. Strategies to improve biodistribution, pharmacokinetic and efficacy of the drug as well as treatment combinations are needed.