Mercury, a prevalent and unrelenting toxin, occurs in a variety of forms in freshwater as well as, in marine life. Mercury is an important inducer of oxidative stress in fish leading to formation of reactive oxygen species. Selenium is an essential micronutrient for animals and has antagonistic effect against mercuric toxicity in fishes. Present study has been made to evaluate toxic effect of HgCl2 (0.15 mg/L) on liver of freshwater catfish Heteropneustes fossilis (Bl.). Protective ability of selenium has been investigated by simultaneous exposure of fish with sodium selenite (0.15 mg/L) along with mercuric chloride. For present study Fishes were divided into three groups of ten fishes each the first group served as control, while the second group fish were exposed to HgCl2. Animals of third group were treated with HgCl2 and Na2SeO3. Results reveal that mercury induced lipid peroxidation and in response to this, antioxidants reduced glutathione (GSH) and Catalase (CAT) were reduced whereas, Glutathione reductase (GR) level was enhanced. These antioxidants scavenge the reactive oxygen radicals. Hg induced histopathological damage and elevation in alkaline phosphatase (ALP) and transaminases and reduction in protein and glucose contents were evidently seen in catfish liver. Intriguingly, results indicate that under stress of mercury, the fish actively generate oxidative stress and antioxidant responses, which can be used as biomarkers of pollution. Simultaneous exposure to Selenium along with Hg suppressed Hg uptake and lipid peroxidation. Histological architecture and all biochemical parameters were maintained near normal in the presence of selenium in liver of the catfish. © 2014 Wiley Periodicals, Inc. Environ Toxicol 30: 927–936, 2015.