Exposure to cadmium and other pollutants is a major environmental problem. Cadmium is causing acute liver injury but the mechanism of hepatotoxicity is poorly understood. The present study aimed to assess the possible reasons by which cadmium causes liver toxicity. Furthermore, the protective role of selenium against this toxicity was investigated. The hepatic level of lipid peroxidation (malondialdehyde, MDA), the antioxidant system (reduced glutathione, glutathione peroxidase, and thioredoxin reductase), as well as the levels of different lipid classes and the fatty acids pattern were determined in three groups of rats of 15 each. The first group (control group) received saline solution intraperitoneal (i.p.) daily for 10 days. The second group (cadmium chloride-treated group) received 2 mg/kg body weight cadmium chloride solution i.p. for a period of 10 days. The third group (cadmium chloride/sodium selenite-treated group) received cadmium chloride as in the second group and received i.p. sodium selenite (1 mg/kg body weight) at the first and sixth day of treatment (two separate injections within 10 days). The results showed that cadmium treatment increased the hepatic level of malondialdehyde (MDA) and the mean percent of total saturated fatty acid in all lipid classes, whereas the levels of antioxidant system, the levels of hepatic cholesterol esters, triglycerides, total phospholipids, mono- and polyunsaturated fatty acids in all lipid classes were decreased compared to control rats. These changes resulting from Cd-treatment were prevented due to treatment of rats with selenium since the levels of reduced glutathione, glutathione peroxidase, and thioredoxin reductase were induced in Se/Cd-treated group compared with either Cd-treated or control group. In addition, selenium maintained the low levels of cholesterol esters, triglycerides, total phospholipids, mono- and polyunsaturated fatty acids in all lipid classes caused by cadmium to their normal levels. It is concluded that cadmium-induced oxidative stress by increasing the levels of free radicals and by decreasing antioxidants level. This oxidative stress could be the primary cause of Cd-induced hepatotoxicity. Also, selenium can be used as a protective agent against Cd-toxicity. This study could provide a possible explanation to hepatotoxicity resulting from exposure to cadmium in the environment. In addition, selenium could ameliorate cadmium-induced hepatotoxicity since it reduced MDA levels and increased the activities of antioxidant enzymes in this tissue.