The high affinity of human plasma β2‐glycoprotein I (β 2 GPI), also known as apolipoprotein‐H (ApoH), for negatively charged phospholipids determines its implication in a variety of physiological pathways, including blood coagulation and the immune response. β 2 GPI is considered to be a cofactor for the binding of serum autoantibodies from antiphospholipid syndrome (APS) and correlated with thrombosis, lupus erythematosus and recurrent fetal loss. We solved the β 2 GPI structure from a crystal form with 84% solvent and present a model containing all 326 amino acid residues and four glycans. The structure reveals four complement control protein modules and a distinctly folding fifth C‐terminal domain arranged like beads on a string to form an elongated J‐shaped molecule. Domain V folds into a central β‐spiral of four antiparallel β‐sheets with two small helices and an extended C‐terminal loop region. It carries a distinct positive charge and the sequence motif CKNKEKKC close to the hydrophobic loop composed of residues LAFW (313–316), resulting in an excellent counterpart for interactions with negatively charged amphiphilic substances. The β 2 GPI structure reveals potential autoantibody‐binding sites and supports mutagenesis studies where Trp316 and CKNKEKKC have been found to be essential for the phospholipid‐binding capacity of β 2 GPI.