Copper oxide was supported on yttria-stabilized zirconia (YSZ) and gamma-alumina, respectively, using impregnation methods. The supported copper oxide catalysts were characterized by temperature-programmed reduction. The catalytic activity of copper oxide supported on YSZ for CO oxidation was measured and compared with those supported on gamma-alumina and with commercial gamma-alumina supported precious metals (PMs) (i.e., Pd and Pt). Results of the activity tests indicated that CuO/YSZ catalysts can exhibit PM-like behaviors such as the light-off characteristic and the hysteresis phenomenon but CuO/gamma-alumina catalysts cannot do so. The significant and conspicuous activity enhancement of the YSZ supported copper oxide has been ascribed to the modification of reaction mechanism due to the surface oxygen vacancy of YSZ. An active center composed of an interfacial Cu+ ion and a surface oxygen vacancy of YSZ and formed by an interfacial metal oxide-support interaction is proposed to explain the activity enhancement. These interfacial active centers could provide a second reaction pathway for CO oxidation via the so-called "metal-support interfacial reaction" step, for which the turnover frequency is much higher than that of redox cycle mechanism operated on the CuO/gamma-alumina catalyst. These interfacial active centers can be destroyed by chlorine addition due to blocking of the surface oxygen vacancies of YSZ by the strongly adsorbed chlorine. The reaction mechanism and catalytic behavior of PM/gamma-alumina, CuO/gamma-alumina, and CuO/YSZ catalysts are compared and discussed.