Reactions of cerium oxide cluster anions with carbon monoxide are investigated by time-of-flight mass spectrometry and density functional theory computations aided with molecular dynamics simulations. Interesting size-dependent reactivity of the Ce_nO_2n+1^– cluster series with n = 1–21 is observed: (1) the small n = 1–3 clusters have no or very low reactivity toward CO, (2) the large n = 4–21 clusters can oxidize CO to produce CO₂, and (3) the n = 4 (Ce₄O₉^–), 6 (Ce₆O₁₃^–), 7 (Ce₇O₁₅^–), and 12 (Ce₁₂O₂₅^–) clusters have relatively higher reactivity than their neighboring systems Ce₃O₇^–, Ce₅O₁₁^–, Ce₈O₁₇^–, etc. Theoretical study indicates that the Ce_nO_2n+1^– clusters contain oxygen-centered radicals (O^–•) and the nature of the spin density distributions within the clusters controls the experimentally observed size-dependent reactivity. The experiment and theory in this study suggest that the metal oxide clusters as large as Ce₂₁O₄₃^– can contain the reactive O^–• centers, at which the size may be large enough to mimic related active sites in condensed phase catalysts. Oxidation of CO by O₂ at low temperature is of widespread importance and reactive oxygen species including O^–• are usually involved. The nature of the O^–• radicals is demonstrated to be able to further address the goodness of nanocrystalline CeO₂ in the low-termperautre CO oxidation.