Two regioisomers with C ₃ or D ₃ symmetry of water-soluble carboxylic acid C ₆₀ derivatives, containing three malonic acid groups per molecule, were synthesized and found to be equipotent free radical scavengers in solution as assessed by EPR analysis. Both compounds also inhibited the excitotoxic death of cultured cortical neurons induced by exposure to N -methyl- d -aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), or oxygen-glucose deprivation, but the C ₃ regioisomer was more effective than the D ₃ regioisomer, possibly reflecting its polar nature and attendant greater ability to enter lipid membranes. At 100 μM, the C ₃ derivative fully blocked even rapidly triggered, NMDA receptor-mediated toxicity, a form of toxicity with limited sensitivity to all other classes of free radical scavengers we have tested. The C ₃ derivative also reduced apoptotic neuronal death induced by either serum deprivation or exposure to Aβ _1–42 protein. Furthermore, continuous infusion of the C ₃ derivative in a transgenic mouse carrying the human mutant ( G93A ) superoxide dismutase gene responsible for a form of familial amyotrophic lateral sclerosis, delayed both death and functional deterioration. These data suggest that polar carboxylic acid C ₆₀ derivatives may have attractive therapeutic properties in several acute or chronic neurodegenerative diseases.