This work provides a detailed insight into the synthesis of N-(2-hydroxypropyl)methacrylamide (HPMA) polymers employing the activated ester approach. In this approach, polypenta fluorophenyl methacrylate (PFPMA)-activated ester polymers are synthesized by the reversible addition-fragmentation chain transfer (RAFT) polymerization and transferred into HPMA-based systems by the use of 2-hydroxypropylamine. To prove quantitative conversion in the absence of side reactions, special attention is devoted to investigate different reaction conditions by different analytical methods (H-1, F-19, inverse-gated C-13 NMR, and zeta potential measurements). Furthermore the influence of common solvent impurities, such as water, is investigated. Besides differences in polymer tacticity, the poly(N-(2-hydroxypropyl) methacrylamide) (PHPMA) synthesized under water-free conditions display the same properties like the conventional synthesized control-PHPMA. However, 3% water content in the dimethylsulfoxide are already sufficient to yield PHPMA polymers with a negative zeta potential of -15.8 mV indication the presence of carboxylic groups due to partial hydrolysis of the activated ester.