A superparamagnetic iron oxide (SPIO) nanoshell and polyvinyl alcohol (PVA) based chemoembolization system for anti-cancer drug doxorubicin (DOX) delivery has previously been presented. We have also previously confirmed the feasibility and safety of this multifunctional system for carrying both DOX and SPIO nanoparticles in vitro. However, the pharmacokinetic and the therapeutic efficacy of this novel drug-delivery system in vivo is not yet clear, and as such was the subject of this study. A rabbit liver tumor model was utilized, whereby the tumors were targeted by SPIO/DOX/PVA composite infused via a catheter into the hepatic arteries which supplying blood to the tumor. The result was compared to saline, DOX+PVA, or SPIO/DOX infusion alone. SPIO/DOX/PVA displayed sustained chemotherapeutic agent release into the tumor. In comparison to other treatment groups, tumor growth rate was significantly slowed down by SPIO/DOX/PVA with a smaller tumor volume and a prolonged survival time of the experimental rabbits. Liver function results demonstrated SPIO/DOX/PVA has no apparent toxicity to the normal liver. Pharmacokinetic studies and histological evaluations in SPIO/DOX/PVA group revealed that long-term retention and drug release within the tumor associated with SPIO/DOX/PVA therapy, and thereafter induced significantly enhanced tumor necrosis and apoptosis. We conclude SPIO/DOX/PVA provides a highly effective therapeutic strategy for management of liver tumors.