Because of the potential application of prodrugs of nonsteroidal anti-inflammatory drugs (NSAIDs), Candida antarctica lipase B (CAL-B) catalyzed polycondensation of profen-containing diol monomers and diesters were designed to prepare a series of biodegradable polymeric prodrugs composed of NSAID branches and poly(amide-co-ester) backbone. The structure of the products was confirmed by Fourier transform infrared spectroscopy, NMR, and gel permeation chromatography (GPC). The reaction conditions of polymerization, such as the enzyme source, amount of catalyst, and temperature, were optimized. The molecular weights of resultant copolymers were 217013,270 g/mol, with corresponding polydispersities from 1.17 to 2.4. The copolymers had relatively high drug loadings of 44.759.7 wt % because every repeat unit contained one drug molecule. The strategy of enzymatic polymerization appeared to be quite general and accommodated a large number of comonomer substrates with various chain lengths and substituents. The optically pure (R)-naproxen monomer was demonstratively incorporated into the corresponding copolymers with the developed synthesis strategy. The in vitro study showed that the polyester could release the drug effectively under physiological conditions with enzyme, which indicated that the obtained product could be a promising prodrug for extending pharmacological effects by delayed drug release. With GPC analysis, we confirmed that the prodrug was completely degradable in aqueous solution. The attractive features of the copolymer were its high drug loading, biodegradability, and biocompatibility. The high tolerance of the CAL-B toward drug groups, as described in this article, provides a new route for synthesizing polymeric drugs with potential biomedical applications in mild conditions and for reducing environmental impact. (c) 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013