Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive dementia. Amyloid-ß peptide (Aß), a 39–43 amino acid peptide derived from ß-amyloid precursor protein, forms insoluble fibrillar aggregates that have been linked to neuronal and vascular degeneration in AD and cerebral amyloid angiopathy. Here we demonstrate that Aß 1–40 and a truncated fragment, Aß 25–35, induced death of oligodendrocytes (OLGs) in vitro in a dose-dependent manner with similar potencies. Aß-induced OLG death was accompanied by nuclear DNA fragmentation, mitochondrial dysfunction, and cytoskeletal disintegration. Aß activation of redox-sensitive transcription factors NF-κB and AP-1 and antioxidant prevention of Aß-mediated OLG death suggest that oxidative injury contributes to Aß cytotoxicity in OLGs. Recent demonstration of Aß deposition and white matter abnormalities in AD implies a potential pathophysiological role for Aß-mediated cytotoxicity of OLGs in this neurodegenerative disease.