Calix[4]arene amide derivatives were employed as new additives within the sol-gel encapsulation of lipase from Candida rugosa (CRL) to improve its catalytic properties. Evaluation of catalytic activity of the encapsulated lipases was acheived by enantioselective hydrolysis of both racemates, Naproxen methyl ester and 2-phenoxypropionic acid methyl ester, in aqueous buffer solution/isooctane reaction system. Results show that enantioselectivity was improved by using calix[4]arene amide derivatives-based encapsulated lipases. The reaction of naproxen methyl ester resulted in 47.6% conversion (x) in 24 h with 88.9% enantiomeric excess of substrate (ees), analogous to an enantioselectivity (E) value of 297 (E = 137 for the encapsulated free enzyme). The conversion of 2-phenoxypropionic acid methyl ester, obtained was 48.4% with E value of 327, enantiomeric excess of substrate (ees) of 92% for the reaction time of 1 h (E = 211 for the encapsulated free enzyme).