The reaction of CO and O2 with submonolayer and multilayer CoOx films on Pt(111), to produce CO2, was investigated at room temperature in the mTorr pressure regime. Using operando ambient pressure X-ray photoelectron spectroscopy and high pressure scanning tunneling microscopy, as well as density functional theory calculations, we found that the presence of oxygen vacancies in partially oxidized CoOx films significantly enhances the CO oxidation activity to form CO2 upon exposure to mTorr pressures of CO at room temperature. In contrast, CoO films without O-vacancies are much less active for CO2 formation at RT, and CO only adsorbed in the form of carbonate species that are stable up to 260 °C. On submonolayer CoOx islands, the carbonates form preferentially at island edges, deactivating the edge sites for CO2 formation, even while the reaction proceeds inside the islands. These results provide a detailed understanding of CO oxidation pathways on systems where noble metals such as Pt interact with reducible oxides.