Using dithioester-capped 2-methacryloyloxyethyl phosphorylcholine (MPC) as a macro chain transfer agent, a diblock copolymer was synthesized with n-butyl methacrylate (BMA) as hydrophobic core-forming blocks. The MPC–BMA unit was copolymerized with an immobilizable unit, p-nitrophenylcarbonyloxyethyl methacrylate (NPMA). The NPMA moiety then was modified by the addition of preS1 domain of hepatitis B surface antigen (HBsAg). This micelle-forming nanoparticle, the poly (MPC-co-BMA-co-NPMA) (PMBN) conjugated with preS1 enables solubilization of paclitaxel (PTX) with increased hepatotropism. The 50% inhibitory concentration (IC50) values of PTX and PTX/PMBN-preS1 against the human hepatocellular carcinoma cell line, HepG2, were 1,008 and 131 nM, respectively (p < 0.05). Conjugation of preS1 to PMBN enhanced strongly the synergistic inhibitory effect of paclitaxel on HepG2 cells in vitro, whereas such a change in IC50 was not detected against the human squamous cell carcinoma cell line, A431. Tumor growth rates of a HepG2 xenograft in Balb/c nude mice after intraperitoneal injection of PTX, PTX/PMBN and PTX/PMBN-preS1 were +97.9%, −74.3% and −96.2%*, respectively (*p < 0.05 versus PTX). The local paclitaxel levels after administration of the PMBN-preS1 conjugate were determined in the xenografts by high-performance liquid chromatography and were 8 times higher than that after administration of paclitaxel alone. No side effects attributable to PMBN-preS1 were observed histologically in vital organs, and body weight loss was significantly less in the PTX/PMBN-preS1 group. These studies demonstrate that PMBN-preS1 may be used as a human hepatocyte-specific drug delivery carrier without serious adverse effects. © 2008 Wiley-Liss, Inc.