We prepared monodisperse Pt2Ru3 nanoparticles supported on carbon black and Sb-doped SnO2 (denoted as Pt2Ru3/CB and Pt2Ru3/Sb-SnO2) with identical alloy composition and particle size distribution by the nanocapsule method. The activities for the hydrogen oxidation reaction (HOR) of these anode catalysts were examined in H2-saturated 0.1 M HClO4 solution in both the presence and absence of carbon monoxide by use of a channel flow electrode at 70 °C. It was found that the CO-tolerant HOR mass activity at 0.02 V versus a reversible hydrogen electrode (RHE) on the Pt2Ru3/Sb-SnO2 electrode was higher than that at the Pt2Ru3/CB electrode in 0.1 M HClO4 solution saturated with 1000 ppm CO (H2-balance). The CO tolerance mechanism of these catalysts was investigated by in situ attenuated total reflection Fourier transform infrared reflection-adsorption spectroscopy (ATR-FTIRAS) in 1% CO/H2-saturated 0.1 M HClO4 solution at 60 °C. It was found, for the Pt2Ru3/Sb-SnO2 catalyst, that the band intensity of CO linearly adsorbed (COL) at step/edge sites was suppressed, together with a blueshift of the COL peak at terrace sites. On this surface, the HOR active sites were concluded to be more available than those on the CB-supported catalyst surface. The observed changes in the adsorption states of CO can be ascribed to an electronic modification effect by the Sb-SnO2 support.