A lipase-catalyzed enantioselective esterification process in cyclohexane was developed for the synthesis of S(+)-naproxen ester prodrugs containing the moiety of N,N-dialkylamino, ethylene glycol or alkyl ether of ethylene glycol. A high enantiomeric ratio of 44 was obtained when di(ethylene glycol) was selected as the best acyl acceptor. A reversible ping-pong Bi Bi mechanism has been employed to elucidate the enzymatic behavior of the initial conversion rate for S(+)-naproxen and the time-course conversions for both enantiomers. Improvement of the enzyme activity was demonstrated when alcohol in excess of its cyclohexane solubility limit was used. The application of excess racemic naproxen in the presence of solid substrate suspensions showed enhanced productivity and enantioselectivity for the desired S(+)-ester. Studies of the recovery and racemization of the remaining R(-)-naproxen are also reported.