Anaerobic CO dehydrogenases catalyze the reversible oxidation of CO to CO 2 at a complex Ni-, Fe-, and S-containing metal center called cluster C. We report crystal structures of CO dehydrogenase II from Carboxydothermus hydrogenoformans in three different states. In a reduced state, exogenous CO 2 supplied in solution is bound and reductively activated by cluster C. In the intermediate structure, CO 2 acts as a bridging ligand between Ni and the asymmetrically coordinated Fe, where it completes the square-planar coordination of the Ni ion. It replaces a water/hydroxo ligand bound to the Fe ion in the other two states. The structures define the mechanism of CO oxidation and CO 2 reduction at the Ni-Fe site of cluster C.