A systematic in vitro biodegradation study of regular poly(ester amide)s (PEAs) composed of naturally occurring hydrophobic alpha-amino acids, fatty diols and dicarboxylic acids using gravimetric (weight loss) method was carried out in the presence of hydrolases like alpha-chymotrypsin, lipase and a complex of proteases of Papaya. The last enzyme was used for modeling the catalytic action of nonspecific proteases. It was found that the PEAs, in the presence of enzyme solutions, were biodegraded by surface chemical erosion mechanism, according to the first-order kinetics. Spontaneous immobilization (adsorption) of the enzymes onto the PEAs surfaces was observed. The surface immobilized enzyme can also catalyze the chemical erosion of the PEAs. The enzymes could also be impregnated into the PEAs to make PEAs biochemically biodegraded, i.e. 'self-destructive', at a target rate. A comparison of in vitro biodegradation data of the PEAs with polylactide (PDLLA) showed that PEAs exhibited a far more tendency toward enzyme catalyzed biodegradation than PDLLA. A preliminary in vivo biodegradation study of selected PEA films in rats with and without lipase-impregnation showed that those PEAs were completely absorbed within 1-2 months post-implantation (for the lipase-impregnated ones) and 3-6 months (for the lipase-free ones). These findings prompt us to suggest that these new PEAs may have a great potential for designing drug sustained/controlled release devices, as well as implantable surgical devices.