Hepatocellular carcinoma (HCC) is one of the most prevalent tumor types, with increased incidence and mortality in recent years. In almost all populations, males have higher HCC rates than females, with male: female ratios usually averaging between 2:1 and 4:1. The reasons for the higher rates of liver cancer in males may be related to sex-specific differences in exposure to risk factors or sex hormones themselves, thus, the present work was designed to study the gender difference of hepatocellular carcinoma. In addition, the study aimed to examine the role of hormonal manipulation in the sequence of this disease in both sexes. This was achieved chemically by a single intra-peritoneal injection of diethylnitrosamine at a dose of 200 mg/kg body weight. This was then followed by single weekly subcutaneous injections of carbon-tetrachloride (CCl4) at a dose of 3ml/kg body weight for 6 weeks. Study groups included: I) Control group of male rats which represented the vehicle-treated, II) Control group of female rats which represented the vehicle-treated, III) The main study group of male rats in which an experimental model of hepatocellular carcinoma (HCC) was induced. This group was randomly subdivided into the following: III A) Group of induced untreated hepatocellular carcinoma, III B) Group of induced hepatocellular carcinoma supplemented with flutamide, IV) The main study group of female rats in which an experimental model of hepatocellular carcinoma (HCC) was induced. This group was randomly subdivided into the following: IV A) Group of induced untreated hepatocellular carcinoma, IV B) Group of induced hepatocellular carcinoma supplemented with tamoxifen, IV C) Group of induced hepatocellular carcinoma supplemented with lutone. All animals were left for a period of 6 weeks which was the time needed for pathogenesis of the disease. Results of the present study observed the existence of gender difference as regards the serum levels of AFP, IGF-1 and inflammatory COX-2 gene expression in addition to the difference in the gene expression for sex hormones' receptors between male and female rats upon induction of HCC. These findings might explain the sex-dependent difference in the disease progression and the fact that the female gender has a distinct survival advantage over the male gender. Moreover, it was clearly observed that modulation of efficacy of sex hormones through their receptors by administration of flutamide in male rats and through supplementation with tamoxifen or lutone in female rats had been associated with a favourable outcome.