Patients with sickle cell disease (SCD) have poorly defined abnormalities of their alternative complement pathway (ACP). We have previously shown chronic activation of the ACP in these patients. To determine the mechanism of this finding, we studied concentrations of the complement control proteins factors I and H in serum from patients with SCD and found no significant difference when they were compared with a control population. Because certain membrane surfaces promote ACP activation and changes occur in erythrocyte membrane phospholipid organization with sickling, we used a liposome model to determine whether ACP activation could be caused by abnormal phospholipid organization of sickle cells. Liposomes with the composition of the sickle cell outer leaflet, which is enriched in phosphatidylserine and phosphatidylethanolamine, activated the ACP significantly more than liposomes with normal outer leaflet phospholipid content. Similarly, liposomes with the composition of the erythrocyte inner membrane leaflet, containing large amounts of phosphatidylethanolamine and phosphatidylserine, activated the ACP more than liposomes with the phospholipid content of the outer leaflet. These findings suggest that phospholipid composition of membranes may play a role in their ability to promote ACP activation, and that changes in phospholipid organization in sickle cells may contribute to the chronic ACP activation observed in patients with SCD.