SARS-CoV-2 infection is associated with a surprising number of morbidities. Uncanny similarities with amyloid-disease associated blood coagulation andfibrinolytic disturbances together with neurologic and cardiac problems led us to investigatethe amyloidogenicity of the SARS-CoV-2 spike protein (S-protein). Amyloidfibril assays of peptide library mixtures and theoreticalpredictions identified seven amyloidogenic sequences within the S-protein. All seven peptides in isolation formed aggregates duringincubation at 37 degrees C. Three 20-amino acid long synthetic spike peptides (sequence 192-211, 601-620, 1166-1185) fulfilled threeamyloidfibril criteria: nucleation dependent polymerization kinetics by ThT, Congo red positivity, and ultrastructuralfibrillarmorphology. Full-length folded S-protein did not form amyloidfibrils, but amyloid-likefibrils with evident branching were formedduring 24 h of S-protein coincubation with the protease neutrophil elastase (NE)in vitro.NEefficiently cleaved S-protein, renderingexposure of amyloidogenic segments and accumulation of the amyloidogenic peptide 194-203, part of the most amyloidogenicsynthetic spike peptide. NE is overexpressed at inflamed sites of viral infection. Our data propose a molecular mechanism forpotential amyloidogenesis of SARS-CoV-2 S-protein in humans facilitated by endoproteolysis. The prospective of S-proteinamyloidogenesis in COVID-19 disease associated pathogenesis can be important in understanding the disease and long COVID-19.