Caffeic acid phenethyl ester (CAPE) is a rare, naturally occurring phenolic food additive. This work systematically reported fundamental data on conversion of caffeic acid (CA), yield of CAPE, and reactive selectivity during the lipase-catalyzed esterification process of CA and phenylethanol (PE) in ionic liquids (ILs). Sixteen ILs were selected as the reaction media, and the relative lipase-catalyzed synthesis properties of CAPE were measured in an effort to enhance the yield of CAPE with high selectivity. The results indicated that ILs containing weakly coordinating anions and cations with adequate alkyl chain length improved the synthesis of CAPE. [Emim][Tf2N] was selected as the optimal reaction media. The optimal parameters were as follows by response surface methodology (RSM): reaction temperature, 84.0 degrees C; mass ratio of Novozym 435 to CA, 14 : 1; and molar ratio of PE to CA, 16 : 1. The highest reactive selectivity of CAPE catalyzed by Novozym 435 in [Emim][Tf2N] reached 64.55% (CA conversion 98.76% and CAPE yield 63.75%, respectively). Thus, lipase-catalyzed esterification in ILs is a promising method suitable for CAPE production.