A family of biodegradable poly(ester amide) (PEA) co-polymers based on naturally occurring alpha-amino acids has been developed for applications ranging from biomedical device coatings to delivery of therapeutic biologics. An important feature of PEA co-polymer coatings may be their ability to promote a natural healing response. To gain insight into this process, representative elastomeric PEAs designed for a cardiovascular stent coating were compared to non-degradable and biodegradable polymers in a series of in vitro assays to examine blood and cellular responses. Each PEA contained L-leucine and L-lysine with the latter derivatized by either benzyl alcohol or the nitroxide radical 4-amino TEMPO as a pendant group. Monocytes adherent to PEA secreted reduced levels of the pro-inflammatory interleukins (IL)-6 and IL-1 beta into the culture supernatant compared to those on comparison polymers but secreted significantly higher amounts of the anti-inflammatory mediator, IL-1 receptor antagonist. As a measure of pro-healing tissue compatibility for cardiovascular applications, endothelial cells adhered, spread, and proliferated on PEA. PEA was also determined to be non-hemolytic and did not deplete platelets or leukocytes from whole blood. ATP release from freshly isolated human platelets on PEA, a measure of their activation, was comparable to the well-known and compatible comparison polymers poly(lactic-co-glycolic acid) and n-poly(butyl methacrylate). Taken together, these in vitro studies of the blood and tissue compatibility of these biodegradable, alpha-amino-acid-based PEAs suggest that they may support a more natural healing response by attenuating the pro-inflammatory reaction to the implant and promoting growth of appropriate cells for repair of the tissue architecture.