The native serpin architecture is extremely sensitive to mutation and environmental factors. These factors induce the formation of a partially folded species that results in the production of inactive loop-sheet polymers. The deposition of these aggregates in tissue, results in diseases such as liver cirrhosis, thrombosis, angioedema and dementia. In this study, we characterize the kinetics and conformational changes of alpha(1)-antitrypsin polymerization at pH 4 using tryptophan fluorescence, circular dichroism, turbidity changes and thioflavin T binding. These biophysical techniques have demonstrated that polymerization begins with a reversible conformational change that results in partial loss of secondary structure and distortion at the top of beta-sheet A. This is followed by two bimolecular processes. First, protodimers are formed, which can be dissociated by changing the pH back to 8. Then, an irreversible conformational change occurs, resulting in the stabilization of the dimers with a concomitant increase in beta-sheet structure, allowing for subsequent polymer extension. Electron microscopy analysis of the polymers, coupled with the far-UV CD and thioflavin T properties of the pH 4 polymers suggest they do not form via the classical loop-beta-sheet A linkage. However, they more closely resemble those formed by the pathological variant M(malton). Taken together, these data describe a novel kinetic mechanism of serine proteinase inhibitor polymerization.