Previous studies have shown that a decoction prepared from a mixture of Nigella sativa seeds, Hemidesmus indicus roots and Smilax glabra rhizome, has the potential to protect against diethylnitrosamine (DEN) induced hepatocarcinogenic changes in rats. The present in-vivo investigation with Wistar rats was conducted to determine whether the treatment with above decoction (6 g / kg / day) for a period of 10 weeks can provide protection against DEN (200 mg / kg by a single i.p. injection) mediated changes in (a) lipid peroxidation, (b) glutathione (GSH) concentration, (c) activities of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx), and (d) activity of the phase II detoxification enzyme glutathione S-transferase (GST). DEN administration resulted in a significant (p<0.05) enhancement (+ 46.2%) of lipid peroxidation (as assessed by formation of thiobarbituric acid reactive substances, TBARS), accompanied by a decreased GSH concentration (- 21.7% in liver; - 5.9% in blood), and activities of SOD (- 34.3%), GPx (- 49.1%) and GST (- 19.38%). Administration of the decoction to DEN treated animals resulted in a significant (p<0.05) reduction in TBARS production, along with a restoration towards the normal levels, of the other biochemical parameters evaluated. The overall results obtained suggests that, protection against DEN - mediated changes in oxidative stress and enhancement of the activities of enzymes participating in carcinogen detoxification are possible mechanisms utilized by the decoction to mediate its anti-hepatocarcinogenic action.