Heating of the serpin Cl-inhibitor above 55°C induced the formation of inactive polymers. Western blotting of non-denaturing gels showed that the polymers bound to the conformation specific monoclonal antibody 4C3, suggesting that a similar conformational change to that occurring in complexed or cleaved inhibitor had taken place. N-Terminal analysis of tryptic peptides which bound to 4C3 showed that the epitope resides within residues 288-444, a region which includes parts of E-sheets A and C. a~-Antichymotrypsin, aa-antiplasmin, angiotensinogen and thyroxine binding globulin also polymerised on heating, indicating that this is a property of many serpins.