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Sickle cell disease is an autosomal recessive genetic red cell disorder with worldwide distribution. Growing evidence suggests a possible involvement of complement activation in the severity of sickle cell clinical complication. Here, we found activation of the alternative complement pathway with microvascular deposition of C5b-9 on skin biopsies from sickle cell disease patients. This was also supported by sickle red cell membrane the deposition of C3b on sickle red cell membranes, which is locally promoted by the exposure of phosphatidylserine. In addition, we showed for the first time a peculiar "stop-and-go" motion of SCD RBCs on TNF-α activated vascular endothelial surfaces. Using the C3b/iC3b binding plasma protein Factor-H as an inhibitor of C3b cell-cell interactions, we found that Factor-H and Factor-H 19-20 domains prevent the adhesion of sickle red cells to the endothelium, normalizing speed transition times of red cells on inflammatory activated endothelium. We have firstly documented that FH acts by preventing the adhesion of sickle red cells to P-selectin and/or the receptor Mac-1 receptor (CD11b/CD18), supporting the activation of the alternative pathway of complement as an additional mechanism in the pathogenesis of acute sickle cell related vaso-occlusive crisis. Our data provide a rationale for further investigation of the potential contribution of Factor-H and other modulators of the alternative complement pathway with potential implications to the treatment of sickle cell disease.