The methylation of catecholate, catalyzed by catechol O-methyltransferase, has been studied by means of ab initio quantum mechanical calculations. The uncatalyzed reaction proceeds via a strongly interacting reactant complex of catecholate and methyl donor and encounters a significant activation barrier. The enzyme active site dictates an alternative orientation of reactants, which leads to a large reduction of activation energy. The contribution of three active-site groups to catalysis has been evaluated from MP2/6-31+G(d,p) interaction energy profiles and ONIOM MP2:HF energies. The calculations indicate that Tyr68 and peptide carbonyl groups of Met40 and Asp141 interact with the reactant complex more strongly than with the transition state. These results suggest that the enormous rate enhancements brought about by catechol O-methyltransferase do not arise from preferential interactions of the transition state with the enzyme. Instead, the catalytic power of this enzyme stems from orienting the reactants into a conformation where little structural rearrangement is needed to form the transition state.