A major cause of clinical disability in multiple sclerosis (MS) is related to a degenerative process in the central nervous system (CNS) which ultimately develops from a potentially reversible inflammation and demyelination. The mechanism of this degenerative process within MS lesions is not completely understood. We hypothesize that oxidative damage to DNA secondary to inflammation may contribute to irreversible tissue alterations in a plaque. To test this assumption, we determined the level of a DNA oxidative marker, 8-hydroxy-deoxy-guanosine (8-OH-dG) in the normal appearing white matter (NAWM), plaque and cortical regions of cerebella from MS patients who suffered from severe cerebellar symptoms during the course of the disease, and in NAWM and cortical regions of cerebella from non-neurological controls. We found a significant increase in DNA oxidation within plaques compared to NAWM specimens in MS cerebella. A tendency for increase of oxidative markers in normal appearing cortical tissues located in the proximity of MS plaques was also observed when compared to those in control cortical specimens. Oxidative damage to DNA in MS lesions, and in neuron rich areas located in the proximity of these lesions is likely related to the release of reactive oxygen species (ROS) and nitric oxide (NO) during inflammation in the brain. This biochemical impairment of DNA and of other macromolecules may contribute to the development of severe clinical disability through the induction of degenerative changes within and outside of plaques in MS brains.