Cardiovascular disease is one of the most serious diseases threatening human health. Puerarin has been widely used in china as a cardiovascular agent. However, a major clinical limitation is its adverse effects of hemolysis. We have addressed this issue by PEGylation and synthesized a puerarin prodrug by covalently linking puerarin to the drug carrier monomethoxy-poly(ethylene glycol) (mPEG). The covalent linkage was validated by UV, FTIR, H-1-NMR, and matrix-assisted laser desorption ionization-time-of-flight mass spectrometry. The hemolysis assay showed that the prodrug produced minimal hematotoxicity. The hydrolysis profile showed that the prodrug was stable in a low pH environment and can continuously release the active drug in physiological condition in vitro. A pharmacokinetic study showed a prolongation of the elimination half-life and a favorable distribution profile in organs, suggesting that the prodrug preparation produced fewer side effects on liver than the injectable form of puerarin normally used. Additionally, the protective effect of the prodrug on acute myocardial ischemia model implied better therapeutic effect than injectable puerarin. We show that the puerarin PEG conjugation is a promising prodrug that produces fewer side effects, exhibits better aqueous solubility, and is more effective than puerarin. (C) 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013