Hepatocellular carcinoma (HCC) is still a leading cause of cancer-related death worldwide. But its chemotherapeutic options are far from expectation. We here compared H-ras targeted genetic therapy to a commercial docetaxel formulation (DXT) in inhibiting HCC in rats. After the physicochemical characterization of phosphorothioate-antisense oligomer (PS-ASO) against H-ras mutated gene, the PS-ASO-mediated in vitro hemolysis, in vivo hepatic uptake, its pharmacokinetic profile, tissue distribution in some highly perfused organs, its effect in normal rats, antineoplastic efficacy in carcinogen-induced HCC in rats were evaluated and compared against DXT treatment. Mutated H-ras expression by in situ hybridization, hep-par-I, CK-7, CD-15, p53 expression patterns by immunohistochemical methods, scanning electron microscopic evaluation of hepatic architecture, various hepatic marker enzyme levels and caspase-3/9 apoptotic enzyme activities were also carried out in the experimental rats. PS-ASO showed low in vitro hemolysis (<3 %), and had a sustained PS-ASO blood residence time in vivo compared to DTX, with a time-dependent hepatic uptake. It showed no toxic manifestations in normal rats. PS-ASO distribution was although initially less in the lung than liver and kidney, but at 8 h it accumulated more in lung than kidney. Antineoplastic potential of PS-ASO (treated for 6 weeks) excelled in inhibiting chemically induced tumorigenesis compared to DTX in rats, by inhibiting H-ras gene expression, some immonohistochemical modulations, and inducing caspase-3/9–mediated apoptosis. It prevented HCC-mediated lung metastatic tumor in the experimental rats. PS-ASO genetic therapy showed potential to inhibit HCC far more effectively than DXT in rats. Display omitted •Antisense oligomer (PS-ASO) increased blood half-life, and time-dependent hepatic uptake and lung accumulation in rats.•It did not show any toxicity in normal rats.•PS-ASO therapy showed superior therapeutic potential to docetaxel in inhibiting hepatocellular carcinoma in rats.•It showed antineoplastic potential, inhibiting H-ras gene expression and inducing caspase-3/9.•PS-ASO also inhibited metastatic tumor development potential of HCC in lungs.