The first step of the reaction of the hydroxide ion with formamide in aqueous solution was studied by high level ab initio calculations and including the solvent effect through the cluster-continuum model. This hybrid discrete/continuum solvation model considers the ion explicitly solvated by some solvent molecules and the bulk solvent is described by a dielectric continuum (PCM). Two and three explicit water molecules solvating the hydroxide ion were included to describe the transition states. Our theoretical activation free energy barrier at 25 °C is 23.4 kcalmol −1 , only 2.2 kcalmol −1 higher than the experimental value of 21.2 kcalmol −1 . We have also investigated a general basic catalysis mechanism, where the hydroxide ion acts as a base and one water molecule in its solvation shell is the nucleophile. Our results indicate that this mechanism does not take place and the real process is the direct nucleophilic attack of the hydroxide ion to the carbonyl carbon.