BACKGROUND AND AIM: To investigate the possible modulating role of "nigella sativa" (NS), a plant commonly used in Egyptian traditional medicine, on premalignant perturbations in three glycol-regulatory enzymes in an experimental rat model of hepatocellular carcinoma (HCC). METHODS: Thirty-six (36) male albino rats were divided into four groups (n = 9). Group 1 served as a normal control, group 2 was treated with methanolic extract of nigella sativa (MENS) (1?g/kg/day, orally) for 14?weeks, group 3 received a single intraperitoneal dose of diethyl nitrosamine (DENA) (200?mg/kg), followed 2?weeks later by a subcutaneous injection of carbon tetrachloride (CCl(4), 3?ml/kg/week/6?weeks) and group IV was treated with MENS for 2?weeks prior to administration of the carcinogenic combination (DENA?+?CCl(4), as in group 3) until the end of the experiment. The total period of the experiment was 14?weeks. RESULTS: In the DENA?+?CCl(4)-treated group, there was a significant increase in the relative liver weight, serum alpha fetoprotein level and the activities of hexokinase, glyceraldehyde phosphate dehydrogenase and glucose 6 phosphate dehydrogenase in both the serum and liver homogenate; this was accompanied by a subsequent decrease in body weight. Pre-treatment with MENS significantly maintained these parameters close to the normal condition. CONCLUSION: Based on these results, we conclude that MENS has a chemo-preventive effect against the progression into liver malignancy through its modulation of the energy metabolic pathways (i.e. glycolysis) that may be involved in hepatocarcinogenesis.