Reaction pathways, solvent effects, and energy barriers have been determined for the base-catalyzed hydrolysis of the benzoyl-ester and methyl-ester groups of neutral cocaine and three smaller alkyl esters in aqueous solution by performing a series of ab initio molecular orbital and density functional theory calculations. The reaction coordinate calculations indicate that both the benzoyl-ester hydrolysis and the methyl-ester hydrolysis occur through a two-step process known for the majority of alkyl esters, i.e,, the formation of a tetrahedral intermediate by the attack of hydroxide oxygen at the carbonyl carbon (first step) followed by the decomposition of the tetrahedral intermediate to products (second step). This is the first first-principles study of the whole reaction pathway for cocaine benzoyl- and methyl-ester hydrolyses. The decomposition of the tetrahedral intermediate requires a proton transfer from the hydroxide/hydroxyl oxygen to the ester oxygen, as the C-O bond between carbonyl carbon and eater oxygen gradually breaks. We have examined two competing pathways for the second step of cocaine hydrolysis: one associated with the direct proton transfer from the hydroxide/hydroxyl oxygen to the ester oxygen, and the other associated with a water-assisted proton transfer. The energy barriers calculated for the second step of the benzoyl- and methyl-ester hydrolyses with water-assisted proton transfer are lower than the first step, whereas with direct proton transfer the barrier for the second step is higher. The first step should be rate-determining for the hydrolysis of both esters in aqueous solution, thus providing theoretical support to the design of the analogues of the first transition state that elicited anti-cocaine catalytic antibodies. The energy barrier, 7.6 kcal/mol, calculated for the first step of benzoyl-ester hydrolysis through the hydroxide attack from the Re face of the carbonyl is similar to1 kcal/mol lower than that through the hydroxide attack from the Si face. The energy barrier, 7.0 kcal/mol, calculated for the first step of cocaine methyl-ester hydrolysis is slightly lower than that of the benzoyl-ester. The effect of substituents on this energy barrier suggests that the transition state is significantly stabilized by hydrogen bonding between the hydroxide oxygen and the beta hydrogen for the carboxylic acid or alcohol moiety.