Lyophilized horseradish peroxidase (HRP) exhibits poor stereoselectivity in the sulfoxidation of thioanisole when the enzyme is either redissolved in water or suspended in organic solvents. However, when HRP is co-lyophilized in the presence of lyoprotectants or ligands, its stereoselectivity, although still low in most organic solvents, increases up to 4-fold if assayed in secondary or tertiary alcohols (but not in their linear isomers). A mechanistic hypothesis is presented explaining this puzzling phenomenon on the basis of a model of the active site of the enzyme-substrate complex derived from its X-ray crystal structure by means of molecular dynamics and energy minimization.