Reactions of CO and O 2 on neutral and anionic Cu 20 clusters have been investigated by spin-polarized density functional theory. Three reaction mechanisms of CO oxidation are explored: reactions with atomic oxygen (dissociated O 2 ) as well as reactions with molecular oxygen, including Langmuir-Hinshelwood (LH) and Eley-Rideal (ER) mechanisms. The adsorption energies, reaction pathways, and reaction barriers for CO oxidation are calculated systematically. The anionic Cu 20 − cluster can adsorb CO and O 2 more strongly than the neutral counterpart due to the superatomic shell closing of 20 valence electrons which leaves one electron above the band gap. The activation of O 2 molecule upon adsorption is crucial to determine the rate of CO oxidation. The CO oxidation proceeds efficiently on both Cu 20 and Cu 20 − clusters, when O 2 is pre-adsorbed dissociatively. The ER mechanism has a lower reaction barrier than the LH mechanism on the neutral Cu 20 . In general, CO oxidation occurs more readily on the anionic Cu 20 − (effective reaction barriers 0.1-0.3 eV) than on the neutral Cu 20 cluster (0.3-0.5 eV). Moreover, Cu 20 − exhibits enhanced binding for CO 2 . From the analysis of the reverse direction of CO oxidation, it is observed that the transition of CO 2 to CO + O can occur on the Cu 20 − cluster, which demonstrates that Cu clusters may serve as good catalyst for CO 2 chemistry. The anionic Cu 20 − cluster can activate O 2 molecule upon adsorption and CO oxidation proceeds efficiently with the dissociated O 2 .