In a previous publication (Ke, T.; Wescott, C. R.; Klibanov, A. M. J. Am. Chem. Sec. 1996, 118, 3366-3374); we discovered and rationalized mechanistically a marked solvent dependence of chymotrypsin＇s prochiral selectivity in the acylation of 2-(3,5-dimethoxybenzyl)-1,3-propanediol with vinyl acetate. In this study, we have answered several important unresolved questions concerning that phenomenon. It has been found that the solvent dependence of prochiral selectivity is dominated by that of (k(cat)/K-M)(pro-R), and this finding has been explained on the basis of a computer modeling analysis of pro-R and pro-S transition-state structures. There is no correlation between the solvent-induced changes of k(cat)/K-M values and those of either k(cat) or K-M individually, presumably reflecting the complex nature of the latter two parameters. Finally, the observed metamorphosis of chymotrypsin from a nonselective to a highly selective catalyst upon variation in the solvent is not attained at the expense of lowered enzymatic reactivity; in fact, prochiral selectivity and catalytic efficiency seem to rise concomitantly.