Lycopene was considered as a major carotenoid in the human diet for only the last few centuries. Recently lycopene has been found to possess chemoprotective effect against gastrointestinal tract, urinary bladder, prostate and breast cancers. In the present study, the protective effect of lycopene, the natural extract from tomato pomace against diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) formation in rats was investigated. Four groups of male albino rats at the age of 6 weeks were studied: 1) control (C), 2) DEN, i.p. injected 5 times with doses of 200 mg/kg b.w., one dose every two days. 3) Lycopene, orally given 0.12 mg/rat/day. 4) Lycopene + DEN, the treatment with lycopene started 7 days before DEN injection and continued till the end of the experimental period. Rats in group 2 and 4 were treated with Phenobarbital (PB) at a dose of 500 ppm in the drinking water as a tumor promoter. PB treatment started with the first injection of DEN and continued till the end of the experimental period. The results indicated that DEN caused HCC nodules as evidenced by a remarkable significant increase in α-L-fucosidase and metalloproteinases (MMPs) enzyme activity in both serum and cytosol. Increased activity of these enzymes is a marker for both preneoplastic and carcinoma lesions. Administration of lycopene prior to DEN injection protected rats from DEN-induced HCC as evidenced by a significant descent in α-L-fucosidase and MMPs enzymes activity in both serum and cytosol. The histological investigation of liver tissue confirmed these results. DEN group showed proliferated hyperplastic and anaplastic hepatocellular nodules surrounded with thin layer of fibroblastic cells, desmoplasia and inflammatory cells infiltrations, focal hepatic haemorrhages and necrosis. Meanwhile, lycopene + DEN group showed no histopathological changes. These results indicate that lycopene effectively inhibits DEN-induced hepatocarcinogenesis in rats.