β-Amyloid (βA) is normally a non-toxic soluble peptide, but in Alzheimer's disease, it aggregates into diffuse and compact plaques, which are associated with neurodegeneration. This study shows that βA neurotoxicity requires the formation of fibrils. Non-fibrillar amorphous aggregates of βA (Am-βA) were not toxic, while fibrillar βA (Fib-βA) caused significant neuronal loss and synapse loss. Congo red, an amyloid fibril-binding dye, inhibited Fib-βA neurotoxicity by either preventing fibril formation or binding to pre-formed fibrils. Congo red also inhibited the toxicity of amylin fibrils, which are associated with diabetes. These findings suggest that amyloid fibrils are toxic and that Congo red may be a potential therapeutic agent for Alzheimer's disease and other amyloidoses. The study highlights the importance of fibril formation in βA toxicity and suggests that inhibiting fibril formation or binding to pre-formed fibrils could be a strategy for treating amyloid-related diseases.β-Amyloid (βA) is normally a non-toxic soluble peptide, but in Alzheimer's disease, it aggregates into diffuse and compact plaques, which are associated with neurodegeneration. This study shows that βA neurotoxicity requires the formation of fibrils. Non-fibrillar amorphous aggregates of βA (Am-βA) were not toxic, while fibrillar βA (Fib-βA) caused significant neuronal loss and synapse loss. Congo red, an amyloid fibril-binding dye, inhibited Fib-βA neurotoxicity by either preventing fibril formation or binding to pre-formed fibrils. Congo red also inhibited the toxicity of amylin fibrils, which are associated with diabetes. These findings suggest that amyloid fibrils are toxic and that Congo red may be a potential therapeutic agent for Alzheimer's disease and other amyloidoses. The study highlights the importance of fibril formation in βA toxicity and suggests that inhibiting fibril formation or binding to pre-formed fibrils could be a strategy for treating amyloid-related diseases.