Administration of 3,4-methylenedioxymethamphetamine (4×20 mg/kg) to non-transgenic CD-1 mice caused marked depletion in dopamine, 3,4-dihydroxyphenylacetic acid and 5-hydroxytryptamine in the caudate–putamen. There were no significant changes in serotonergic markers in the hippocampus and frontal cortex. Homozygous and heterozygous copper/zinc superoxide dismutase transgenic mice show partial protection against the toxic effects of 3,4-methylenedioxymethamphetamine on striatal dopaminergic markers. In addition, 3,4-methylenedioxymethamphetamine injections caused marked decreases in copper/zinc superoxide dismutase activity in the frontal cortex, caudate–putamen and hippocampus of wild-type mice. Moreover, there were concomitant 3,4-methylenedioxymethamphetamine-induced decreases in catalase activity in the caudate–putamen and hippocampus, decreases in glutathione peroxidase activity in the frontal cortex as well as increases in lipid peroxidation in the frontal cortex, caudate–putamen, and hippocampus of wild-type mice. In contrast, administration of 3,4-methylenedioxymethamphetamine to homozygous superoxide dismutase transgenic mice caused no significant changes in antioxidant enzyme activities nor in lipid peroxidation. These results provide further substantiation of a role for oxygen-based radicals in 3,4-methylenedioxymethamphetamine-induced neurotoxicity. The present data also suggest that free radicals generated during 3,4-methylenedioxymethamphetamine administration may perturb antioxidant enzymes. Consequently. there might be further overproduction of free radicals with associated peroxidative damage to cell membranes and associated terminal degeneration.