A new family of positively charged and water soluble amino acid-based poly(ester amide)s (PEAs) consisting of nontoxic L-arginine, diols, and aliphatic dicarboxylic acids building blocks was synthesized and characterized. The L-arginine based PEAs (Arg-PEAs) were prepared by a solution polycondensation of two monomers: tetra-p-toluenesulfonic acids salts or hydrochloride acid salts of bis-(L-arginine) alpha, omega-alkylene diesters (monomer II), and di-p-nitrophenyl esters of saturated or unsaturated dicarboxylic acids (monomer I). Optimal reaction conditions were studied as functions of type of solvents and acid acceptors, concentrations of reactants. The molecular weights (Mn and Mw) of Arg-PEAs measured by GPC ranged from 20,000 to 60,000 g mol-1 with a rather narrow molecular weight distribution below 1.5. The chemical structures were confirmed by IR and NMR spectra. Arg-PEAs obtained were all amorphous materials with Tg from 33 to 125 degrees C, depending on the number and the type (saturated vs. unsaturated) of methylene groups in diols or diacids, and the type of counter-ions attached to the guanidine group of the Arg-based PEAs. The Arg-PEAs had a high solubility in all polar solvents, including water. Preliminary studies of cell morphology and DNA capture capability of Arg-PEAs indicated that this new family of cationic PEAs was nontoxic and more biocompatible than a commercial transfection agent (Superfect (R)), and can successfully capture plasma DNA. The strong positive charge of Arg-PEAs as well as their good water solubility could provide unique characteristics for potential gene transfection or other charge preferred biomedical applications. (C) 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012