Sickle cell anemia (SCA) is characterized by a number of variations in the clinical course of the disease process. A significant number of studies suggest that the inter-patient clinical variations may be a consequence of the relative proportion of dense sickle RBCs present in the circulation. Our recent studies demonstrate that dense sickle erythrocyte (RBC) subpopulations, contain several Ig-binding RBC subsets. The origins and pathophysiologic role of these circulating RBC subsets is unknown. To provide a bases for investigations which address these questions the present study will characterize the phenotypes of the individual dense sickle cell subsets by (a) determining the biochemical identity of Ig- binding membrane proteins; (b) defining correlations between non-Ig- binding RBC membrane markers and intracellular HbF; and (c) defining correlations between intracellular HbF and the identity of either IgG, IgM or IgA binding sites present on RBC components of specific Ig-binding dense subsets. These data are correlated with the proportion of reticulocytes, irreversibly sickled cells (ISCs) and nonISCs, content of each of the Ig-binding dense sickle cell subsets isolated by flow cytometric cell sorting; and compared with data derived from parallel analyses of low-density paired samples and dense normal(AA) RBCs. A separate set of studies will determine whether the proportionate distribution and phenotype of Ig-binding sickle RBC subsets is altered after hydroxyurea therapy, and identify specific sickle cell subsets most sensitive to this agent.