A nanoparticle formulation of docetaxel (DTX) was designed to address the strengths and limitations of current taxane delivery systems: PEGylation, high drug conjugation efficiency (>30 wt %), a slow-release mechanism, and a well-defined and stable nanoparticle identity were identified as critical design parameters. The polymer conjugate was synthesized with carboxymethylcellulose (CMC), an established pharmaceutical excipient characterized by a high density of carboxylate groups permitting increased conjugation of a drug. CMC was chemically modified through acetylation to eliminate its gelling properties and to improve solvent solubility, enabling high yield and reproducible conjugation of DTX and poly(ethylene glycol) (PEG). The optimal conjugate formulation (Cellax) contained 37.1 ± 1.5 wt % DTX and 4.7 ± 0.8 wt % PEG, exhibited a low critical aggregation concentration of 0.6 μg/mL, and formed 118-134 nm spherical nanoparticles stable against dilution. Conjugate compositions with a DTX degree of substitution (DS) outside the 12.3-20.8 mol % range failed to form discrete nanoparticles, emphasizing the importance of hydrophobic and hydrophilic balance in molecular design. Cellax nanoparticles released DTX in serum with near zero order kinetics (100% in 3 weeks), was internalized in murine and human cancer cells, and induced significantly higher toxic effects against a panel of tumor cell lines (2- to 40-fold lower IC50 values) compared to free DTX.