The catalytic role of the PtFe cation ensemble presented at the perimeters of the FeO film supported on Pt(111) for low-temperature CO oxidation and the promotion of water on activity were studied by using DFT calculations. We found that the perimeter sites along the edge of the FeO islands on Pt provided a favorable ensemble that consisted of coordinatively unsaturated ferrous species and nearby Pt atoms for O2 and H2O activation free from CO poison. A dissociative oxygen atom at the PtFe cation ensemble reacts easily with CO adsorbed on nearby Pt. The OH group from water dissociation not only facilitates activation of the oxygen molecule, more importantly it opens a facile reaction channel for CO oxidation through the formation of the carboxyl intermediate. The presence of the OH group on the FeO film strengthens interfacial interactions between FeO and Pt(111), which would make the FeO film more resistant to further oxidation. The importance of the PtFe cation ensemble and the role of water as a cocatalyst for low-temperature CO oxidation is highlighted.