Oligomerization of human cystatin C (HCC) leads to amyloid deposits in brain arteries, and this process is greatly accelerated with a naturally occurring L68Q variant. The crystal structures of N-truncated and full-length HCC (cubic form) showed dimer formation via three-dimensional (3D) domain swapping, and this observation has led to the suggestion that an analogous domain-swapping mechanism, but propagated in an open-ended fashion, could be the basis of HCC fibril formation. Here we report that full-length HCC, when crystallized in a new, tetragonal form, dimerizes by swapping the same secondary structure elements but with a very different overall structure generated by the flexibility of the hinge linking the moveable elements. The β-strands of the β-cores of the two folding units of the present dimer are roughly parallel, while they formed an angle of about 100° in the previous two structures. The dimers pack around a crystallographic dyad by extending their molecular β-sheets in an intermolecular context. At the other edge of the molecular β-sheet, side-chain–side-chain hydrogen bonds propagate the β-structure in the same direction. In consequence, a supramolecular crystal structure is generated, with all the β-strands of the domain-swapped dimers being perpendicular to one crystallographic direction. This observation is relevant to amyloid aggregation of HCC, as X-ray diffraction studies of amyloid fibrils show them to have ordered, repeating structure, consistent with the so-called cross-β structure, in which extended polypeptide chains are perpendicular to the fiber axis and form infinite β-sheets that are parallel to this axis. Proteins 2005. © 2005 Wiley-Liss, Inc.