Senile plaques in the cerebral parenchyma are a pathognomonic feature of Alzheimer's disease (AD) and are mainly composed of aggregated fibrillar amyloid β (Aβ) proteins. The plaques are associated with neuronal degeneration, lipid membrane abnormalities, and chemical evidence of oxidative stress. The view that Aβ proteins cause these pathological changes has been challenged by suggestions that they have a protective function or that they are merely byproducts of the pathological process. This investigation was conducted to determine whether Aβ proteins promote or inhibit oxidative damage to lipid membranes. Using a mass spectrometric assay of oxidative lipid damage, the 42-residue form of Aβ (Aβ42) was found to accelerate the oxidative lipid damage caused by physiological concentrations of ascorbate and submicromolar concentrations of copper(II) ion. Under these conditions, Aβ42 was aggregated, but nonfibrillar. Ascorbate and copper produced H 2 O 2 , but Aβ42 reduced H 2 O 2 concentrations, and its ability to accelerate oxidative damage was not affected by catalase. Lipids could be oxidized by H 2 O 2 and copper-(II) in the absence of ascorbate, but only at significantly higher concentrations, and Aβ42 inhibited this reaction. These results indicate that the ability of Aβ42 to promote oxidative damage is more potent and more likely to be manifest in vivo than its ability to inhibit oxidative damage. In conjunction with prior results demonstrating that oxidatively damaged membranes cause Aβ42 to misfold and form fibrils, these results suggest a specific chemical mechanism linking Aβ42-promoted oxidative lipid damage to amyloid fibril formation.