The time and dose-dependent effects of kainic acid (KA) induced excitotoxicity on the oxidative defense system and the relationship to the induction of stress proteins were investigated in the rat hippocampus. Male Long-Evans rats were injected subcutaneously with 5.0, 7.5, or 10 mg KA/kg. Rats were sacrificed and the hippocampus removed and processed for biochemical and electrophoretic analysis. The activity of glutathione peroxidase (GPx) increased significantly at the 5 mg KA/kg dose, while malondialdehyde (MDA) levels significantly increased at 7.5 mg KA/kg when measured at 24 h. A dose of 10 mg KA/kg depleted significantly hippocampal glutathione (GSH) levels at 8, 16 and 24 h post-treatment while GPx activity was increased significantly at 2, 4, 8 and 16 hr post-treatment. The 10 mg KA/kg increased significantly hippocampal MDA levels at 2 h post-treatment and decreased significantly thereafter. The induction of stress proteins increased in a dose and time dependent manner. The expression of Hp72 and Hsp32 increased significantly at 16 h with a maximum induction observed at 24 h post-treatment. The data suggests that KA toxicity is mediated through the formation of reactive oxygen species resulting in alterations in the oxidative defense system. The expression of stress proteins following KA administration may reflect a concomitant but alternate response to excitotoxic events.