Penicillin amidase was shown to catalyze the transesterification of phenoxyacetic acid methyl ester (POME) with 1-propanol in organic solvents. The enzyme was found to be over 750-fold more reactive in hexane upon lyophilizing in the presence of KCl (to produce an enzyme preparation containing 98% (w/w) salt and 1% (w/w) each of enzyme and phosphate buffer), and 225-fold activation in the more hydrophilic acetonitrile. This activation was strongly dependent on solvent hydration so that in tert-amyl alcohol containing 3% (v/v) added water, the salt-containing preparation was two-fold slower than the salt-free preparation. This behavior was opposite of that observed with the known lyoprotectant trehalose, indicating that salt activation is mechanistically distinct from lyoprotection. This work represents the first demonstration of dramatic salt activation of a nonprotease.