Carboxyfullerenes, including two regioisomers C3 and D3, were investigated as antioxidants against iron-induced oxidative stress in vivo and in vitro. Both C3 and D3 dose-dependently inhibited autoxidation and iron-elevated lipid peroxidation in cortical homogenates. The antioxidative property of C3 was compared to Trolox (a water-soluble analogue of vitamin E) and glutathione. C3 was more effective than glutathione but was less effective than Trolox in inhibiting iron-induced elevation in lipid peroxidation. In urethane-anesthetized rats, intranigral infusion of iron degenerated the nigrostriatal dopaminergic system, including as elevation in lipid peroxidation in the infused substantia nigra (SN) and reductions in K(+)-evoked dopamine overflow and dopamine content in the ipsilateral striatum 7 days after the infusion. Local application of iron with C3 or D3 prevented iron-induced oxidative injuries. Our data suggest that carboxyfullerenes have a neuroprotective effect in preventing iron-induced oxidative injury in CNS.