To assess whether fetal hemoglobin (HbF) modulates the adhesion of sickle erythrocytes to endothelium, children with homozygous sickle cell anemia (SS disease) were studied, using this physiologically crucial period to evaluate the relationships between HbF and the major erythrocyte adhesion markers. The mean level of CD36(+) erythrocytes was 2.59% +/- 2.15% (+/- SD, n = 40) with an inverse relationship between CD36 positivity and F cells (R = -0.76, P < .000 00 002). In univariate analyses, significant correlations with various hematologic parameters and age were noted. Multiple regression analyses, however, revealed a relationship solely with F cells. Minimal levels of very late activation antigen-4(+) (VLA4(+)) erythrocytes (0.31% +/- 0.45%, n = 40) with relationships similar to those noted for CD36(+) cells were also observed. The subpopulation of strongly adhesive stress reticulocytes was further assessed, using CD71 as their marker. The mean level of CD71(+) erythrocytes was 5.81% +/- 4.21%, with statistical correlates in univariate and multivariate analyses similar to those discussed above. When adhesion ratios were evaluated, inverse correlations were noted between basal and plasma-induced adhesion and F-cell numbers (R = -0.54, P < .0005; R = -0.53, P < .0006, n = 39). In addition, in analyses where basal or plasma-induced adhesion was the dependent variable and the independent variables included F cells and the various adhesion-related parameters, significant relationships solely with F cells were noted. The results demonstrate that SS patients with higher levels of F cells have concomitant decreases in the numbers of CD36(+), VLA4(+), and CD71(+) erythrocytes and that these findings translate into less adherent erythrocytes. These findings extend knowledge regarding the protective effects of HbF in the pathophysiology of sickle cell disease.