The reactive site loop of the serpin family of serine proteinase inhibitors is flexible and can adopt a number of diverse conformations. A 2.9 Å resolution structure of α1-antitrypsin—the principal proteinase inhibitor in human plasma—shows the loop in a stable canonical conformation matching that found in all other families of serine proteinase inhibitors. This unexpected finding in the absence of loop insertion into the body of the molecule favours a two-stage mechanism of inhibition and provides a model for the heparin activation of antithrombin. The β-pleated strand conformation of the loop also accounts for the polymerization of the serpins in disease and for their association with other β-sheet structures, most notably the β-amyloid of Alzheimer's disease.