We studied 33 patients with sickle-cell anemia to examine the possible relation between the severity of their disease (frequency of microvascular occlusions) and the abnormal adherence of sickle erythrocytes to cultured human endothelium. Neither clinical severity nor erythrocyte adherence correlates significantly with red-cell indexes, hemoglobin concentration, percentage of irreversibly sickled red cells, level of fetal hemoglobin, or reticulocyte count. However, clinical severity and erythrocyte adherence are strongly correlated (rank correlation coefficient =+0.666; P<0.001). These findings are consistent with the hypothesis that abnormal interactions between erythrocytes and endothelium may be the initiating factor in the development of microvascular occlusions in sickle-cell anemia. (N Engl J Med. 1980; 302:9925.) THE polymerization of deoxygenated sickle hemoglobin (Hb S) is generally felt to be the primary causal factor in the complex pathophysiology of sickle-cell anemia. However, the exact relation between the intracellular polymerization of Hb S, the consequent sickling of erythrocytes, and the protean clinical manifestations of this disease remains a mystery. Specifically, an explanation for the great variability in clinical severity among patients, despite their genotypic and hematologic similarity, has remained elusive and is an area of continuing investigation.1 2 3 4 5 6 The microvascular occlusions characteristic of sickle-cell anemia have been assumed to be a direct consequence of the relative circulatory incompetence of.