In a sequence of molecular orbital calculations, employing the iterative extended Hückel theory, we have studied a simple molecular model for key aspects of the catalytic process at the active site of hen egg white lysozyme, in its hydrolytic cleavage of a bacterial cell wall mucopolysaccharide. The sequence of calculations was designed to simulate "snapshots" of the interacting groups of atoms, along a reaction pathway proposed by others on the basis of such data as X-ray diffraction and model-building. For comparison with the uncatalyzed reaction, we did calculations on the same sequence without the model enzyme. The calculated activation energy of the catalyzed reaction is 0.51 eV less than for the uncatalyzed reaction, predicting a rate increase due to the enzyme by a factor of 4 × 108. The calculated changes in charge densities and bond densities support quite clearly the proposal that the catalytic mechanism begins with the action of the glu 35 residue as a general acid catalyst, the major factor in the rate-determining formation of a stable carbonium ion intermediate.