Leucocytes are emerging as critical determinants in the severity of the pathology associated with sickle cell disease (SCD) and recent studies have shown that they can bind to sickle red blood cells (SS RBCs). However, the mechanism of this interaction is unclear. The α4β1 integrin on monocytes and SS reticulocytes was found to mediate the interaction of these cells in in‐vitro adhesion assays and in the blood of SCD patients. Plasma fibronectin (Fn), a ligand for α4β1, could link SS RBCs to monocytes, as peptides derived from both the Arg‐Gly‐Asp‐Ser (RGDS) and CS‐1 site in Fn disrupted the reticulocyte/monocyte interaction. It was further shown in whole blood that 70% of the interacting monocytes were also bound to platelets, suggesting the existence of multi‐cellular aggregates in SCD. Platelet inclusion in these aggregates was mediated by a P‐selectin/P‐selectin glycoprotein ligand‐1 interaction, which has been demonstrated to activate the monocyte. These results suggest a new model for understanding the mechanism of attachment of SS RBCs to monocytes and implicate the platelet as a component and contributor to potentially occlusive aggregates that circulate in the blood of SCD patients.