Experiments were performed to explore whether adhesion differences among different density sickle (SS) cells are mainly caused by deformability characteristics attendant to density variations, which could affect their surface contacts with the endothelium, or caused by any changes in their membrane surface (eg, receptors). Also, what is the contribution of morphologic attributes of SS cells in adhesive and obstructive events? To resolve these issues, controlled modifications of cell density were performed using Nystatin and sucrose. This allowed elevation of the mean corpuscular hemoglobin concentration (MCHC) of light-density SS2 discocytes to that of SS4 native dense cells, as well as its normalization in both native and artificially dehydrated cells. Hemodynamic and adhesive characteristics of these individual SS cell populations and their defined mixtures were investigated in the ex vivo mesocecum vasculature. Dehydrated (high MCHC) SS2 discocytes, alone or with SS2 control cells, caused a higher peripheral resistance but no persistent microvascular blockage. Nevertheless, dehydrated SS2 discocytes resulted in a significantly decreased adhesion in venules (adhesion sites). Rehydration of these high MCHC discocytes completely restored their adhesivity, similar to that of SS2 control cells. In contrast, irreversibly sickled cell (ISC)-rich SS4 dense cell class (dense discocytes and 66% to 72% ISCs) was less adherent than dehydrated SS2 discocytes, but caused a persistent blockage of small diameter postcapillary venules when infused with SS2 control or dehydrated discocytes. In the areas of adhesion, SS4 dense discocytes outnumbered ISCs by 4 to 1, demonstrating that ISCs, because of their shape characteristics, are minimally adherent but play a distinct role in postcapillary obstruction. When MCHC (density) of SS4 cells was decreased by rehydration, it resulted in an almost complete reversal of their hemodynamic and adhesive behavior, confirming a profound influence of cell density. These findings demonstrate for the first time that, under shear flow, adhesion of different density SS cells to the endothelium is dependent on the inverse of cell density rather than any changes in their adhesion potential. Finally, the trapping of ISC- rich native dense cells, but not of dehydrated discocytes, in the areas of adhesion shows a distinct contribution of ISC in adhesion-initiated vasoocclusion.