There is a large body of literature indicating that aggregated amyloid-beta peptide (Abeta) is toxic to neurons and suggesting that this neurotoxicity represents the final common pathway for neuronal degeneration in Alzheimer's disease. Previous studies have shown the outgrowth of a subclone of the rat neuronal cell line PC12 that is resistant to the toxic effect of aggregated Abeta peptide if the parent cell line is grown in the presence of aggregated Abeta peptide for a number of passages [Behl, Davis, Lesley and Schubert (1994) Cell 77, 817-827; Boland, Behrens, Choi, Manias and Perlmutter (1996) J. Biol. Chem. 271, 18032-18044]. To begin to characterize the mechanism by which PC12 cells become resistant to the apoptotic effect of Abeta peptide, in the present study we examined whether the resistance was specific to aggregated peptides, specific to an apoptotic form of cell death, and specific in cell type or was a general resistance to cell death that could be elicited in diverse cell types. The results show that the resistance is specific to compounds that have apoptotic effects through the generation of hydroxyl radical or H2O2, including aggregated Abeta-(25-35), Abeta-(1-40), Abeta-(1-42), Abeta-(1-43), amylin, 6-hydroxydopamine and H2O2 itself. The resistant subclones of PC12 were not resistant to other forms of apoptotic cell death or to necrotic cell death. The resistant state was also identified in a human hepatoma cell line, HepG2, when it was grown in the presence of aggregated Abeta-(25-35) for several passages, indicating that the mechanism(s) or molecule(s) responsible for this resistance are not restricted to neuronal cells and may be relevant to the pathobiology of oxidative injury in other cell types.