The aim of this study was to investigate the possible protective role of lycopene, as a natural antioxidant and anticancer, against hepatotoxicity induced by administration of flutamide (10, 100, and 300 mg/kg) for 60 days in male Wistar albino rats (Rattus rattus). Obtained results showed significant increase in malondialdehyde (MDA), the marker of lipid peroxidation; marked decreases in the levels of glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT), the major antioxidant markers, in the liver of rats treated with flutamide. The drug also markedly lowered serum contents of total proteins (TP), albumin (ALB) and high density lipoprotein-cholesterol (HDL-C) in treated rats. On the other hand, activities of alanine aminotransferase (ALT), aspartate amino-transferase (AST), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH); and levels of total bilirubin (TB), total lipid (TL), total cholesterol (TC), triglycerides (TG), and low density lipoprotein-cholesterol (LDH-C) in serum were elevated. Flutamide-induced adverse effects were dose-dependent, and suggested incidence of oxidative tissue damage in the liver of used rats. However, treatment with lycopene (10 mg/kg) markedly reduced the deleterious effects of flutamide on the investigated parameters, particularly in low dose-treated rats. Lycopene treatment alone at applied dose level seemed to be safe, non-toxic to the monitored biochemical indices. These data indicate that the natural antioxidant lycopene may has a protective effect against flutamide-induced hepatotoxicity in male R. rattus. Further studies are needed to investigate the hepatoprotective effect of lycopene during therapy with flutamide in patients with prostate cancer.