This paper reports on the resolution of (R,S)-2-(4-methylphenyl) propionic acid (MPPA) enantiomers by enzymatic esterification in organic solvent. Novozym 435 (CALB) has the best catalytic performance compared with other lipases. Of the alcohols screened, n-hexanol is the best acyl acceptor and gives the highest enzyme activity and enantioselectivity in n-hexane. Response surface methodology (RSM) was used to evaluate the influence of the factors, such as temperature, enzyme amount, substrate concentration and reaction time on the substrate conversion (c) and enantiomeric excess (ee). The correlation coefficient R2 for enantiomeric excess and the conversion are 0.9827 and 0.9910, respectively, indicating that can accurately predict the experimental results. By simulation and optimization, the optimal conditions were obtained, involving 600 mmol·L?1 MPPA concentration (0.60 mmol), 850 mmol·L?1 hexanol concentration (0.85 mmol), 58 mg enzyme amount, 75 ℃ temperature and 4.5 h reaction time, respectively. Under the optimized conditions, the experimental values of conversion and enantiomeric excess were 89.34％and 97.84％, respectively, which are in good agreement with the model predictions.