Background: Worldwide, consistent survival benefit for chemotherapy in hepatocellular carcinoma (HCC) is a golden goal for concerned researchers. Nexavar® (sorafenib) is the only approved agent that achieved touchable successes in this regard. Thus, there is a pressing medical need for new promising drugs to improve HCC therapy. Aims: our designed lactosaminated albumin conjugate of doxorubicin (L-HSA–DOXO) that rapidly and preferentially accumulates in the liver is compared, for the first time at its MTD, with doxorubicin and sorafenib, not only for antitumor efficacy but also for overall survival. Methods: HCC was induced in male Wistar rats with N-nitrosodiethylamine added to drinking water (100 mg/L) for 8 weeks. Endpoints were antitumor efficacy, tolerability and overall survival. Results: L-HSA–DOXO proved to be superior at least over doxorubicin in the majority of assessed endpoints. Circulating AFP-L3% was diminished in L-HSA–DOXO (14.5%) and sorafenib (18.4%) groups compared to DENA (31.1%) and doxorubicin (29.5%) groups. This superiority was further confirmed by Western blot analyses of some novel HCC biomarkers. Survival study reinforced consistent benefits of both L-HSA–DOXO and sorafenib. Conclusions: L-HSA–DOXO shows at least comparable activity to sorafenib which clinically achieves only ∼3 months overall survival benefit. Combination of these two agents could act beneficially or synergistically via two different modes of action to fight HCC.