The catalytic properties of copper(II) oxide powders were studied in the CO oxidation reaction by using plug-flow and flow-circulation reactors. Data obtained from different catalytic experiments were in good agreement with each other. The specific catalytic rate [molecules cm−2 s−1] increased by a factor of approximately four if the surface area of the CuO powder was reduced from 90 to 8 m2 g−1. A further decrease in the CuO surface area to 1 m2 g−1 resulted in the decrease of the specific CO oxidation rate by more than 20-fold. These results indicate that CO oxidation is sensitive to the structure of the copper(II) oxide catalyst. The structural sensitivity of CuO powders was discussed in terms of its defect structure and particle morphology.