LmACR2 is the first identified antimonate reductase responsible for the reduction of pentavalent antimony in pentostam to the active trivalent form of the drug in Leishmania. LmACR2 is a homologue of the yeast arsenate reductase Acr2p and Cdc25 phosphatases and has the HC[X]5R phosphatase motif. Purified LmACR2 exhibited phosphatase activity in vitro and was able to dephosphorylate a phosphotyrosine residue from a synthetic peptide. This phosphatase activity was inhibited by classical inhibitors such as orthovanadate. LmACR2-catalyzed phosphatase activity was inhibited by either antimonate or arsenate. Site-directed mutagenesis experiments showed that the H74C[X]5R81 motif was involved in catalysis. This is the first report of a metalloid reductase with a bifunctional role in protein tyrosine phosphatase activity. Leishmania is never exposed to metalloids during its life cycle. It is therefore unlikely that it would evolve an enzyme exclusively for drug activation. We propose that the physiological function of LmACR2 is to dephosphorylate phosphotyrosine residues in leishmanial proteins.