A new, quantitative model is elaborated to rationalize the solvent dependence of enzymatic selectivity solely on the basis of the thermodynamics of substrate solvation. The model predicts that any type of the selectivity (defined as the ratio of k(cat)/K-M values) should be proportional to the ratio of the thermodynamic activity coefficients of the desolvated portions of the substrate(s) in the relevant transition state of the enzymatic reaction. The latter ratio is calculated by (i) determining the desolvated portion of the substrate in the transition state using molecular modeling based on the crystal structure of the enzyme, (ii) approximating this desolvated portion of the substrate by a distinct model compound, and (iii) calculating the activity coefficient of this model compound using the UNIFAC computer algorithm. In this study, the developed general model has been applied to, and verified with, prochiral selectivity of enzymes. Crystals (lightly cross-linked with glutaraldehyde) of gamma-chymotrypsin or subtilisin Carlsberg used as asymmetric catalysts in organic solvents almost quantitatively adhere to the predictions of the model in the acetylation of 2-substituted 1,3-propanediols. In contrast, little agreement between the predicted and observed solvent dependences of the prochiral selectivity has been obtained with lyophilized or acetone-precipitated chymotrypsin, thus confirming that the enzyme structure in such preparations (but not in crystals) is non-native.