Kinetic and isotopic data are used to interpret the mechanistic role of gaseous H2O molecules and of non-reducible (Al2O3) and reducible (TiO2, Fe2O3) supports on CO oxidation turnovers catalyzed by small Au clusters (<5 nm). H2O acts as a co-catalyst essential for O-2 activation and for catalyst stability in CO oxidation at near-ambient temperatures, but also inhibits rates via competitive adsorption at higher H2O pressures. The effects of CO, O-2, and H2O pressures on CO oxidation turnover rates, the absence of O-16(2)/O-18(2) v and O-16(2)/(H2O)-O-18 exchange, and the small H2O/D2O kinetic isotope effects are consistent with quasi-equilibrated molecular adsorption of CO, O-2, and H2O on Au clusters with the kinetic relevance of H2O-mediated O-2 activation via the formation of hydroperoxy intermediates ((OOH)-O-center dot), which account for the remarkable reactivity and H2O effects on Au clusters. These elementary steps proceed on Au clusters without detectable requirements for support interface sites, which are no longer required when H2O is present and mediates O-2 activation steps. Rate enhancements by H2O were also observed for CO oxidation on Pt clusters (1.3 nm), which is also limited by O-2 activation steps, suggesting H2O-aided O-2 activation and (OOH)-O-center dot species in oxidations involving kinetically-relevant O-2 activation. These intermediates have also been proposed to account for the ability of O-2/H2O mixtures to act as reactants in alkene epoxidation on Au-based catalysts. Published by Elsevier Inc.