The effect of oxygen vacancy on the enhancement of activity of CO-NO-O-2 reaction over yttria-stabilized zirconia (YSZ)-supported CuO catalyst was investigated in the present study. The catalysts were prepared by the impregnation method, and their characteristics were studied by temperature-programmed reduction. The catalyst was placed in a flow reactor for performing the temperature-programmed reaction, and the effluent gas was analyzed by an on-line NOx analyzer, consisting of a chemiluminescence unit and two gas chromatographs in series. The present results indicate that copper oxide supported by YSZ exhibits a higher catalytic activity than that supported by alpha-Al2O3, for the CO-NO-O-2 reaction. The enhanced activity is inferred to result from the formation of interfacial Cu2O and the oxygen-ion transfer. Additionally, the probable effect of oxygen vacancy in promoting the CO-O-2 or CO-NO2 reaction has been elucidated by a mechanism involving oxygen-ion transfer via surface oxygen vacancies of YSZ, which are located at the interface between CuO and YSZ. It was found that the CuO/YSZ catalyst is a promising substitute for the conventional Rh/alumina catalyst.