beta-Amyloid (beta A) is normally produced as a nontoxic soluble peptide. In Alzheimer disease, beta A aggregates and accumulates in the brain as inert diffuse plaques or compact plaques associated with neurodegenerative changes. To determine the relationship of neurotoxicity to the physical state of beta A, we created (i) nonamyloidogenic amorphous aggregates of beta A [amorphous beta A (Am-beta A)] analogous to diffuse plaques and (ii) amyloidogenic fibrils of beta A [fibrillar beta A (Fib-beta A)] analogous to compact plaques. In primary rat hippocampal culture, Fib-beta A was neurotoxic, whereas Am-beta A was not toxic. Fib-beta A caused significant loss of synapses in viable neurons, while Am-beta A had no effect on synapse number. The amyloid fibril-binding dye Congo red inhibited Fib-beta A neurotoxicity by inhibiting fibril formation or by binding to preformed fibrils. Congo red also inhibited the pancreatic islet cell toxicity of diabetes-associated amylin, another type of amyloid fibril. These results indicate that beta A neurotoxicity requires fibril formation. These findings and our previous demonstration that amylin fibrils are toxic suggest that a common cytopathic effect of amyloid fibrils may contribute to the pathogenesis of Alzheimer disease and other amyloidoses.