To explore the effects of cadmium (Cd) exposure of tilapia (Oreochromis niloticus) on hepatic glutathione (GSH) metabolism, tilapias were exposed to 3.0 mg/L Cd for 1, 5, 10, 20, and 40 days. The contents of reduced GSH and oxidized GSH (GSSG) and the activities of enzymes involved in GSH metabolism and the GSSG-GSH ratio were investigated. The results showed that reduced GSH were depleted progressively whereas the GSSG-GSH ratio increased. The activities of selenium-dependent glutathione peroxidase, glutathione S-transferase and glucose-6-phosphate dehydrogenase, and GSSG levels increased initially and decreased subsequently but still higher than the controls. Glutathione reductase activity dropped on the 40th day. A transient increase in gamma-glutamylcysteine syntheses activity was detected on the 20th day. The findings demonstrated that the hepatic GSH pool showed different reaction patterns associated with exposure period. The homeostatic mechanism was activated by short-term Cd exposure while the response ability weakened for a longer exposure.