The amyloid plaque in Alzheimer's disease (AD) contains numerous proteins, some of which may be relevant to the pathogenesis of the disease. The serine protease inhibitor α1-antichymotrypsin is specifically localized in AD plaques. It is shown here that α1-antichymotrypsin and several other serine protease inhibitors (serpins) inhibit the toxicity of amyloid peptides on primary cortical nerve cell cultures as well as a clonal cell line. This inhibition of toxicity is not mediated via the serpin enzyme complex receptor, the transferrin receptor, or by interference with the polymerization of amyloid fibrils. Since a variety of synthetic serine protease inhibitors mimic the effects of serpins on amyloid toxicity, it is likely that the antiprotease activities of serpins are responsible for their biological effects.