Abstract: Oxidation of the drug guaifenesin by a Ag(III) complex anion, [Ag(HIO6)2]5-, was studied in aqueous alkaline medium by using spectrophotometry. The major oxidation product of guaifenesin was identified by mass spectrometry. The oxidation reaction displayed an overall second-order kinetics: first-order with respect to both Ag(III) and guaifenesin. Variations of [OH-] and [IO-4]tot had a significant influence on the reaction rates, where [IO-4]tot denotes the total concentration of periodate added externally. An empirical rate expression, k′=(ka+kb[OH-])K1/{f([OH-])[IO-4]tot+K1}, was derived, where ka=(2.6±1.2)×10-2 mol-1·L·s-1, kb=(2.8±0.1) mol-2·L2·s-1, and K1=(4.1±0.4)×10-4 mol·L-1 at 25.0 ℃ and ionic strength of 0.30 mol·L-1. Activation parameters associated with ka and kb were also derived. A mechanism involving the [Ag(HIO6)(OH)(H2O)]2- as the reactive species of the oxidant was proposed. Guaifenesin and the reactive species reversibly formed a complex, which decomposed by two parallel slow steps to give rise to the products: one pathway was spontaneous and the other was assisted by a hydroxide ion.