The architecture of the native human alpha(2)-macroglobulin was studied by cryoelectron microscopy and image processing techniques. The lip, padlock, doughnut, and four-petaled flower views of this homotetrameric proteinase inhibitor were observed in the frozen-hydrated specimen, and a new view, termed eye view, was also characterized. The present three dimensional reconstruction demonstrates that all these electron microscope views derive from a single three-dimensional structure. The molecule is composed of two horizontal bodies and of two oblique arches, which border a large central cavity. The polymorphism and the flexibility of the native alpha(2)-macroglobulin are discussed. (C) 1994 Academic Press, Inc.