A promising approach to improve drug delivery is the chemical transformation of active drug substances into per se inactive prodrugs that convert to parent compounds via enzymic or chemical lability in the body. However, a major problem for the general application of this principle is the limited availability of chemical derivative types satisfying prodrug requirements, most notably reconversion to the parent drug in vivo. Esters are well-known prodrugs due to the ready availability of hydrolytic enzymes in the organism, but many aliphatic or aromatic esters are not sufficiently labile in vivo. For example, simple alkyl and aryl esters of penicillins are not hydrolyzed to the active free penicillin acid in vivo, rendering them therapeutically ineffective. Similarly, the methyl or ethyl esters of naproxen and fenbufen show much reduced antiinflammatory activity compared to their free acids due to resistance to in vivo hydrolysis. In the field of angiotensin-converting enzyme inhibitors, ethyl esters like enalapril (a clinically used prodrug of enalaprilic acid) are not hydrolyzed by plasma enzymes, requiring liver-mediated conversion, and pentopril (another ethyl ester prodrug) shows less than 50% in vivo deesterification to the active acid. While double ester types (e.g., (acyloxy)alkyl or [(alkoxycarbonyl)oxy]alkyl esters) can overcome some of these shortcomings by exhibiting higher enzymatic lability than simple alkyl esters, their utility is limited by poor water solubility, limited in vitro stability, and often being oils that pose formulation challenges. In an effort to explore new generally applicable ester prodrug types with high susceptibility to enzymatic hydrolysis in plasma or blood, we discovered that esters of certain 2-hydroxyacetamides (glycolamides) are cleaved with remarkable speed in human plasma. This paper reports that these rather simple esters may be a promising prodrug type for drugs containing a carboxylic acid function and that it is feasible to obtain ester derivatives with almost any desired hydrophilicity or lipophilicity while still maintaining a high rate of enzymatic hydrolysis.