Docetaxel (DTX) remains the only effective drug for prolonging survival and improving quality of life of metastatic castration resistant prostate cancer (mCRPC) patients. Despite some clinical successes with DTX-based therapies, advent of cumulative toxicity and development of drug resistance limit its long-term clinical application. The integration of nanotechnology for drug delivery can be exploited to overcome the major intrinsic limitations of DTX therapy for mCRPC. We evaluated whether reformulation of DTX by facile conjugation to carboxymethylcellulose nanoparticles (Cellax) can improve the efficacy and safety of the drug in s.c. and bone metastatic models of CRPC. A single dose of the nanoparticles completely regressed s.c. PC3 tumor xenografts in mice. In addition, Cellax elicited fewer side effects compared to native DTX. Importantly, Cellax did not increase the expression of drug resistance molecules in androgen-independent PC3 prostate cancer cells in comparison with DTX. Lastly, in a bone metastatic model of CRPC, Cellax treatment afforded a 2- to 3-fold improvement in survival and enhancements in quality-of-life of the animals over DTX and saline controls. These results demonstrate the potential of Cellax in improving the treatment of mCRPC.