Novel anti-oxidants based on the buckminsterfullerene molecule were explored as neuroprotective agents in cortical cell cultures exposed to excitotoxic and apoptotic injuries. Two polyhydroxylated C₆₀derivatives, C₆₀(OH)_n,n= 12, and C₆₀(OH)_nO_m,n= 18–20,m= 3–7 hemiketal groups, demonstrated excellent anti-oxidant capabilities when tested by electron paramagnetic spectroscopy with a spin-trapping agent and a hydroxyl radical-generating system. These water-soluble agents decreased excitotoxic neuronal death following brief exposure to NMDA (by 80%), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA; by 65%), or kainate (by 50%). Electrophysiology and tracer⁴⁵Ca²⁺-uptake studies verified that buckminsterfullerenols are not NMDA or AMPA/kainate receptor antagonists. Buckminsterfullerenols also reduced neuronal apoptosis induced by serum deprivation. These results support the idea that oxidative stress contributes to both excitotoxic and apoptotic neuronal death, and furthermore suggest that fullerenols represent a novel type of biological anti-oxidant compound.