Polymer-drug conjugation to highly water-soluble and biocompatible polymers, such as poly(2-methacryloyloxyethyl phosphorylcholine) (polyMPC), imparts excellent aqueous solubility, improved pharmacokinetics, and reduced off-target toxicity, together providing opportunities to enhance the antitumor efficacy of small molecule chemotherapeutics. We are developing a novel polyMPC-based prodrug system incorporating temozolomide (TMZ) intended for treating glioblastoma, a highly aggressive and infiltrative brain cancer. Using a versatile TMZ-methacrylate, well-defined and water-soluble polyMPC-TMZ random and block copolymers were prepared by controlled free radical polymerization over a broad range of drug incorporations (15-50 mole percent TMZ). The solution properties of the conjugates were investigated by dynamic light scattering and transmission electron microscopy, showing nanoscale aggregates of the block copolymers. Conjugation to a polymer backbone significantly enhanced the aqueous stability of pendent TMZ moieties, as demonstrated by UV-vis spectroscopy under physiological conditions. Cell culture experiments in both chemosensitive and chemoresistant glioblastoma cell lines showed both architecture- and drug loading-dependent cytotoxicity of the prodrugs.