The immobilized lipase Novozym 435 was used as catalyst, toluene was used as solvent, and 4? molec-ular sieve was added to catalyze the esterification reaction of isosorbide and hexanoic acid to prepare isosorbide dihexanoate (SDH). Four factors (reaction time, reaction temperature, enzyme addition amount, 4? molecular sieve dosage) were selected by single factor experiment for response surface analysis. The results showed that the yield of isosorbide dihexanoate was 93.77 % under the optimal conditions of toluene 10 mL, n ( isosorbide ) = 0.03 mol, n ( isosorbide ) ∶ n ( caproic acid ) = 1 ∶ 6, reaction time 43 h, reaction temperature 40 °C, immobilized lipase Novozym 435 0.1 g and 4? molecu-lar sieve 2 g.