The design of new generation cardiovascular biomaterials focuses on biomimetic properties that are capable of eliciting specific cellular responses and directing new tissue formation. Synthetic poly(ester amide)s (PEAs) containing alpha-amino acid residues have the potential to elicit favorable cellular responses. Furthermore, they are biodegradable owing to the incorporation of naturally occurring amino acids. In this study, a family of PEAs was synthesized from selected alpha-amino acids using both solution and interfacial polymerization approaches to optimize their properties for vascular tissue engineering applications. By careful selection of the monomers and the polymerization approach, high-molecular-weight PEAs with low glass-transition temperatures were obtained. Human coronary artery smooth muscle cells (HCASMCs) cultured directly on bare PEA films attached and spread well up to 7 days of culture. Moreover, cell viability was significantly enhanced on all nonfunctional PEAS compared with tissue culture polystyrene controls. The trifluoroacetic acid salt of the lysine-containing functional PEAs was found to retard cell growth but still supported cell viability up to 5 days of culture. Irnmunostaining of HCASMCs revealed strong vinculin expression, suggesting that the HCASMCs initiated cellular processes for focal adhesion contacts with all PEA surfaces. Conversely, smooth muscle alpha-actin expression was not abundant on the PEA surfaces, suggesting a proliferative smooth muscle cell phenotype. Altogether, our results indicate that these PEAs are promising materials for vascular tissue engineering scaffolds.