Water adsorbed at the metal-support interface (MSI) plays an important role in multiple reactions. Due to its importance in CO preferential oxidation (PrOx), we examined H-2 oxidation kinetics in the presence of water over Au/TiO2 and Au/Al2O3 catalysts, reaching the following mechanistic conclusions: (i) O-2 activation follows a similar mechanism to that proposed in CO oxidation catalysis; (ii) weakly adsorbed H2O is a strong reaction inhibitor; (iii) fast H-2 activation occurs at the MSI, and (iv) H-2 activation kinetics are inconsistent with traditional dissociative H-2 chemisorption on metals. Density functional theory (DFT) calculations using a supported Au nanorod model suggest H-2 activation proceeds through a heterolytic dissociation mechanism, resulting in a formal hydride residing on the Au and a proton bound to a surface TiOH group. This potential mechanism was supported by infrared spectroscopy experiments during H-2 adsorption on a deuterated Au/TiO2 surface, which showed rapid H-D scrambling with surface hydroxyl groups. DFT calculations suggest that the reaction proceeds largely through proton-mediated pathways and that typical Bronsted-Evans Polanyi behavior is broken by introducing weak acid/base sites at the MSI. The kinetics data were successfully reinterpreted in the context of the heterolytic H-2 activation mechanism, tying together the experimental and computational evidence and rationalizing the observed inhibition by physiorbed water on the support as blocking the MSI sites required for heterolytic H-2 activation. In addition to providing evidence for this unusual H-2 activation mechanism, these results offer additional insight into why water dramatically improves CO PrOx catalysis over Au.