2,5‐Diketopiperazines (DKPs) are the smallest cyclic dipeptides found in nature with various attractive properties. In this study, we have demonstrated the successful modification of proline‐based DKPs using anionic ring‐opening polymerization (AROP) as a direct approach. Four different proline‐based DKPs with various side chains and increasing steric hindrance were used as initiating species for the polymerization of 1,2‐epoxybutane or ethoxyethyl glycidyl ether in the presence of t‐BuP4 phosphazene base. The addition of a Lewis acid, tri‐isobutyl aluminum, to the reaction mixture strongly decreased the occurrence of side reactions. Impact of the DKP side‐chain functionalities on molar mass control and dispersity was successfully evidenced. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 1008–1016 Proline‐based 2,5‐diketopiperazines (cyclic dipeptides) are used in the presence of aphosphazene base as anionic ring‐opening polymerization initiators of two epoxide monomers, 1,2‐epoxybutane or protected glycidol (ethoxyethylglycidyl ether). Addition of Lewis Acid to the reaction mixture strongly decreases the occurrence of side reactions and allows the synthesis of 100% DKP‐functionalized polymer chains. [ABSTRACT FROM AUTHOR]