To find effective agents for Parkinson's disease (PD) prevention and therapy, we examined the protective effects of the polyhydroxylated fullerene derivative C(60)(OH)(24) in a 1-methyl-4-phenylpyridinium (MPP(+)) -induced acute cellular PD model in human neuroblastoma cells and the free radical scavenging effects in this model with an electron spin resonance (ESR) spectrometer. Pretreatment with C(60)(OH)(24) at concentrations greater than 20 microM showed significant protective effects on MPP(+) -induced loss in cell viability, decreases in mitochondrial function (including mitochondrial membrane potential and activities of complex I and II), and increases in the levels of reactive oxygen species and oxidative damage to DNA and proteins. In addition, C(60)(OH)(24) acts as a phase 2 enzyme inducer to protect cells from MPP(+) -induced decreases in expression of nuclear factor-E2-related factor 2, expression and activity of gamma-glutamyl cysteine ligase and level of glutathione. The ESR study showed that C(60)(OH)(24) is a powerful radical scavenger for superoxide, hydroxyl, and lipid radicals. These data suggest that C(60)(OH)(24) is a mitochondrial protective antioxidant with direct radical scavenging activity and indirect antioxidant inducing activity.