ANNEXINS are a family of calcium- and phospholipid-binding proteins(1,2) implicated in a number of biological processes including membrane fusion(3) and ion channel formation(4-7). The crystal structure of the annexin XII hexamer, refined at 2.8 Angstrom resolution, forms a concave disk with 3-2 symmetry, about 100 Angstrom in diameter and 70 Angstrom thick with a central hydrophilic pore. Six intermolecular Ca2+ ions are involved in hexamer formation. An additional 18 Ca2+ ions are located on the perimeter of the disk, accessible only from the side of the hexameric disk. On the basis of the hexamer structure we propose here a new mode of protein-phospholipid bilayer interaction that is distinct from the hydrophobic insertion of typical membrane proteins. This speculative model postulates the Ca2+-dependent insertion of the hydrophilic annexin XII hexamer into phospholipid bilayers with local reorientation of the bilayer phospholipids.