The purpose of this investigation was to evaluate the effects of lead (Pb) and lead + zinc (Zn) combination on the oxidative stress, total ATPase and Pb accumulation in the tissues of Oreochromis niloticus (Linnaeus, 1758). The fish were exposed to 0.1 mg/L Pb (T1), 1.0 mg/L Pb (T2) and mixtures of 0.1 mg/L Pb and 0.5 mg/L Zn (M1); 1.0 mg/L Pb and 5.0 mg/L Zn (M2) for 7 and 21 days. Pb accumulation, total ATPase activity, several antioxidant enzyme activities such as catalase, glutathione peroxidase (GPX), glutathione S-transferase, glutathione reductase, and thiobarbituric acid reactive substances concentrations were measured in the liver and kidney tissues. Metal accumulation in the tissues was higher in Pb exposure compare with mixtures of Pb and Zn exposures. Beside the inhibition of liver GPX activity, general increases of antioxidant enzyme activities in the tissues were recorded after metal exposures. This investigation emphasizes the oxidative stress in O. niloticus caused by Pb, and adaptation of the organisms to the changes in enzyme activities.