Intraperitoneal injection of [Gd@C 82 (OH) 22 ] n nanoparticles decreased activities of enzymes associated with the metabolism of reactive oxygen species (ROS) in the tumor-bearing mice. Several physiologically relevant ROS were directly scavenged by nanoparticles, and lipid peroxidation was inhibited in this study. [Gd@C 82 (OH) 22 ] n nanoparticles significantly reduced the electron spin resonance (ESR) signal of the stable 2,2-diphenyl-1-picryhydrazyl radical measured by ESR spectroscopy. Likewise, studies using ESR with spin-trapping demonstrated efficient scavenging of superoxide radical anion, hydroxyl radical, and singlet oxygen ( 1 O 2 ) by [Gd@C 82 (OH) 22 ] n nanoparticles. In vitro studies using liposomes prepared from bovine liver phosphatidylcholine revealed that nanoparticles also had a strong inhibitory effect on lipid peroxidation. Consistent with their ability to scavenge ROS and inhibit lipid peroxidation, we determined that [Gd@C 82 (OH) The endohedral metallofullerenes recently attracted significant attention because of their special biomedical effect as chemotherapeutic medicines (Cagle et al., 1999;Chen et al., 2005). Endohedral metallofullerenol nanoparticles ([Gd@C 82 (OH) 22 ] n ) could efficiently inhibit the proliferation of tumors and decrease the activities of enzymes related to reactive oxygen species (ROS) generation in vivo, but the molecular mechanism is still unclear (Wang et al., 2006). ROS such as superoxide radical anion, hydrogen peroxide, singlet oxygen, and hydroxyl radicals have been implicated in the etiology of a wide range of acute and chronic human diseases, including amyotrophic lateral sclerosis, arthritis, cancer, cardiovascular disease, and several neurodegenerative disorders (Valko et al., 2007). Accordingly, species that have a strong capacity for scavenging ROS are of great Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org. . , superoxide radical anion; 1 O 2 , singlet oxygen; DPPH, 2,2-diphenyl-1-picrylhydrazyl; rBCEC, rat brain capillary endothelial cell; DMPO, 5,5-dimethyl-1-pyrroline N-oxide; AAPH, 2,2Ј-Azobis(2-amidinopropane) dihydrochloride; PBS, phosphatebuffered saline; JC-1, 5,5Ј,6,6Ј-tetrachloro-1,1Ј,3,3Ј-tetraethylbenzimida-zolylcarbocyanine iodide; ⌬⌿ m , mitochondrial membrane potential; CM-H 2 DCFDA, 5-(and 6-)-chloromethyl-2Ј,7Ј-dichlorodihydrofluorescein diacetate, acetyl ester.