The hydrolytic degradation under physiological conditions of a series of poly(ester amide)s prepared from 1,n-amino alcohols and aliphatic dicarboxylic acids including succinic, glutaric, and tartaric acids was examined. Degradability was observed to increase with the content in ester groups. Poly(ester amide)s containing tartaric acid were found to be highly sensitive to hydrolysis while those not containing four-car bon diacid units appeared to be fairly stable. It was also found that degradation of both poly(succinester amide)s and poly(tartarester amide)s critically depended on the regicity of the polymer chain. Whereas isoregic poly(ester amide)s were easily degraded, the syndioregic polymers displayed a great resistance to the action of water. Aregic poly(tartarester amide)s degraded even faster than isoregic polymers. The products resulting from hydrolysis were investigated by both FTIR and NMR spectroscopy. A set of model compounds including ester and amides of L-tartaric acid was synthesized and subjected to hydrolysis to help in the interpretation of the degradation mechanism taking place in poly(tartarester amide)s. It was concluded that chain scission in both isoregic and aregic poly(ester amide)s must take place by intramolecular amidolysis with formation of either succinimide or tartarimide units. This mechanism requires the presence of four-carbon diacid units in the poly(ester amide), and it is unable to operate if the polymer chain has an entirely syndioregic microstructure. The results are relevant to the design of sequential poly(ester amide)s with controlled hydrodegradability.