Various potential mechanisms for the alkaline hydrolysis of an oxo-beta-lactam in the gas phase (Scheme 1) were examined in the light of ab initio data obtained at the RHF/G-31+G*//RHF/G-31+G* and MP2/6-31+G*//MP2/6-31+G* levels. The influence of the solvent was also examined from IPCM (isodensity polarizable continuum model) computations at the RHF/6-31+G* level. In penicillins and cephalosporins, alkaline hydrolysis begins with a nucleophilic attack on the carbonyl group of the beta-lactam ring, which is followed by cleavage of the C-7-N-4 bond. In the oxo-beta-lactam studied, the process additionally involves cleavage of the C-7-O-6 bond in the ring. In fact, this cleavage is subject to a very small activation energy, as little as 0.21 kcal/mol versus the 14.15 kcal/mol for the typical cleavage energy (based on MP2/6-31+G*//MP2/6-31+G* calculations) for the C-7-N-4 bond. In addition, the hydrolysis end products are more stable than those resulting from the typical cleavage. Consequently, the alkaline hydrolysis involving cleavage of the C-7-O-6 bonds is kinetically and thermodynamically more favorable than the classical hydrolysis mechanism for penicillins and cephalosporins. This suggests that oxo-beta-lactams might act as beta-lactamase inhibitors.