This study is intended to determine the effect of lead acetate on glutathione and its associated enzymes of rat brain. Wistar male rats were treated with lead acetate (500 ppm) through drinking water for a period of 8 weeks and parallel controls were maintained. They were sacrificed at the first, fourth and eighth week to isolate whole brains, which were separated into cerebellum, hippocampus, frontal cortex and brain stem. The data indicate enhanced (P < 0.05) glutathione peroxidase (G-Px) activity at most of the intervals for cerebellum, frontal cortex and brain stem, suggesting conversion of GSH to GSSG, while the hippocampus showed decreased levels. In contrast, glutathione reductase (GR) decreased significantly (P < 0.05) in cerebellum, frontal cortex and brain stem at all intervals except the fourth week in frontal cortex and brain stem. Hippocampus exhibited a gradual and significant (P < 0.05) increase in GR activity. Glutathione-S-transferase (GSTase) activity increased with exposure time in all four brain tissues, showing protection against lead acetate toxicity. The GSH and GSSG levels correlated well with the activities of GPx, GR and GSTase in all four regions of the brain. Overall the results indicate that lead acetate affects glutathione-related enzymes differentially and these changes can be attributed to differences in tissue susceptibility.