The erythrocytes deliver oxygen to all around body cells that make them extremely vital for the metabolism. Metals are transferred through the blood, meaning the erythrocytes face with metals continuously. The present study intended to explore the responses of osmoregulation (Na+/K+-ATPase, Mg2+-ATPase, Ca2+-ATPase) and antioxidant system parameters (CAT, SOD, GPX, GR, GST, tGSH, rGSH, GSSG, GSH/GSSG) in the erythrocytes of the Nile tilapia (Oreochromis niloticus) following acute (20 mu M, 2 d) and sub-chronic (10 mu M, 20 d) Cd and Pb exposures. ATPases were more sensitive compared to the antioxidant system parameters. All ATPase activities increased significantly in acute and sub-chronic metal exposures. Variations in antioxidant system parameters were recorded with metal and duration differences, Pb causing more alterations. GSH metabolism was mostly altered, especially after sub-chronic Pb exposure, though CAT and GPX activities decreased. Acute Pb exposure also caused a decrease in GPX activity and an increase in GST activity. There were differences in GSH/GSSG ratios between acute and sub-chronic Pb exposures. Cd caused few alterations in the antioxidant system parameters (GSSG and GSH/GSSG ratio decrease and GST increase). The present study demonstrated that the osmoregulation and antioxidant systems of the erythrocyte are sensitive to metal exposures and may provide useful data about the stress fish face.