<p>Global environmental issues drive the development of sustainable materials. Water-soluble polymers with tunable degradability have the potential to displace conventional nondegradable counterparts. Poly(trimethylene carbonate) (PTMC) analogs are promising candidates for functionalized hydrolyzable polymers, including those with water-soluble functionality. Recently, the hydration properties conferred by side chains have been shown to promote the hydrolysis of PTMC analogs. Additionally, the amide linker in the side chain facilitates interactions with water and may catalyze hydrolysis via hydrogen-bond activation of water and main-chain carbonate bonds. Herein, we report the hydrolytic behavior of previously developed water-soluble PTMC analogs and discuss their relationship to their hydration properties. The PTMC analogs are designed to have two hydroxy groups on the side chain arranged in different configurations, thereby enabling high water solubility. The dihydroxy-functionalized PTMC analogs degrade in water within a few days in phosphate-buffered saline (PBS), whereas under alkaline conditions, the polymers degrade within 1 h. Differential scanning calorimetry of the hydrated PTMC analogs indicates that dihydroxy side chains efficiently facilitate the formation of intermediate water. This study demonstrates that enhancing hydration through side-chain engineering promotes the hydrolysis of PTMC analogs, thereby enabling the polymer lifetime to be tuned from hours to weeks.</p>