CO oxidation activity was measured at atmospheric pressure and at temperatures of 300 to 450-degrees-C over copper catalysts supported on 6.8 mol% Yttria-stabilized zirconia (YSZ). Fresh, high-temperature reduced with CO, and reoxidized catalysts were investigated using two reacting atmospheres, oxygen lean and oxygen rich. Temperature-programmed reduction using CO as reducing gas was employed to characterize the dispersion and the copper oxide species of catalysts before and after the reaction. Results were discussed in light of the occupancy of surface oxygen vacancies of YSZ support by copper atoms, the penetration of copper atoms into bulk oxygen vacancies of YSZ support, and the interfacial Cu2O formation owing to surface oxygen vacancies of YSZ support. These also suggest that geometric interfacial metal-support interaction can enhance the activity of copper catalyst by improving the dispersion and stabilizing the interfacial Cu2O through the oxygen vacancies of support. A mechanism in which oxygen vacancies of YSZ support can protect the interfacial Cu2O to avoid further reduction or oxidation has been proposed. The occurrence of penetration, redispersion, and split of copper species crystallites has also been explained by an oxygen vacancy model.