Antiphospholipid antibody formation can be induced in mice by phospholipid in a hexagonal II phase but not by phospholipid in a bilayer phase. Since sickle red cell membranes have increased hexagonal II phase content, we have measured serum antiphospholipid antibody levels in 25 patients with sickle cell disease to determine whether anti-phospholipid antibody may similarly be induced in these patients. Seventeen of the 25 patients (68%) had increased levels of antiphospholipid antibodies. Eleven patients (65%) had IgG and six each (35%) had IgM and IgA isotypes. Antiphosphatidylethanolamine, antiphosphatidylserine, antiphosphatidylinositol, and antiphosphatidic acid were the most frequently increased antibodies. The finding of increased antiphospholipid antibodies in these patients is compatible with the concept that antiphospholipid antibody formation is associated with structural changes in the red cell membrane and that such structural changes occur in the red cells of patients with sickle cell disease.