The hallmark of sickle cell disease (SCD) is vasoocclusive crisis (VOC). The sickle red blood cells (SS-RBCs) present enhanced adhesion to activated endothelial cells (ECs) as compared to normal RBCs (AA-RBCs) and believed to contribute to VOC. Hydroxycarbamide (HC), the sole drug thus far proven as efficacious at reducing VOC frequency, alters the expression of adhesion proteins both on RBCs and ECs. We investigated the functional effect of HC on the adhesive properties of ECs from the micro- or the macrocirculation (TrHBMEC, HPMEC, and HUVEC). Using a flow chamber, we analyzed RBC dynamics on the treated or untreated EC bed and firm adhesion in basal and inflammatory conditions. Most significant effects were obtained with ECs from the pulmonary microcirculation (HPMEC). HC treatment of ECs affects both transient interactions and firm adhesion of SS-RBCs to the EC bed. Indeed, first, HC-treatment of ECs decreases the number of firmly adherent SS-RBCs to the adhesion level of AA-RBCs in a VCAM-1 independent manner. Second, HC significantly increases the mean velocity of SS-RBCs and reduces the population of SS-RBCs in contact with the EC bed. These data provide additional evidence that modulation of SS-RBCs/ECs interactions by HC represents an important aspect of its mechanism of action.