This study was carried out to investigate the potential effects of sublethal concentration (5 mg.L -1 ) of combined heavy metals (1.25 mg.L -1 of each) including cadmium (Cd), copper (Cu), lead (Pb) and zinc (Zn) on Nile tilapia, Oreochromis niloticus after exposure for 1, 3, 5 and 7 days in order to evaluate the protective role of vitamin E and combination of selenium (Se) with vitamins A, C and E against the toxicity of these heavy metals. Exposure of O. niloticusto heavy metals only for 1, 3, 5 and 7 days resulted a significant increase in the values of antioxidant enzymes (GSH, CAT, GST, GR and GPx) in liver and gills of O. niloticus. While the exposure to the mixture of heavy metals and vitamin E or heavy metals with selenium protected the liver and gill of O. niloticus. The activities of antioxidant substances and free radicals (SOD, GSH, GSSG, TAC and MDA) formation were also determined after 1, 3, 5 and 7 days of exposure to heavy metals only or heavy metals with vitamin E or selenium. Antioxidants (both enzymatic and nonenzymatic) can provide protection against deleterious metal-mediated free radical attacks. Vitamin E and combination of selenium (Se) with vitamins A, C and E prevent the majority of metal-mediated (Cd, Cu, Pb, and Zn) damage. Therefore, this study confirms on the powerful protective potential of the antioxidants vitamin E alone and a combination of selenium with vitamins A, C and E against the toxicity of Cd, Cu, Pb and Zn on O. niloticus.