Density functional theory (DFT) and microkinetic modeling are used to examine the water-gas shift (WGS) reaction on TiO2(110)-supported single Pt atoms. A CO-adsorbed Pt atom supported on a TiO2 surface exhibits a lower activity for the WGS than the Pt2+ ion supported on a doped TiO2 surface, although DFT predicts the CO-adsorbed Pt on an undoped TiO2 surface to be thermodynamically more stable. Trends observed in WGS activity for different active sites of TiO2-supported Pt catalysts can be explained in terms of CO adsorption strength and the ability to form an oxygen vacancy on the oxide support.