Increased exposure of sickle red blood cells to phosphatidylserine promotes its adhesion to the endothelium. A monoclonal antibody to lactadherin, a phosphatidylserine binding protein, inhibits sickle cell adhesion to histamine-stimulated endothelial cells in flowing blood. Added lactadherin enhances the adhesion via the integrin αVβ3. These results indicate that lactadherin can mediate phosphatidyl-serine-expressing sickle cell adhesion to the endothelium.