While many studies of erythropoiesis have focused on interactions between developing cells and the extracellular matrix, scant attention has been paid to the role of erythroid-macrophage interactions in this process. Murine erythroleukemia (MEL) cell lines have been used extensively in these studies to define erythroid adhesion events. In this study, we compared the adhesion to both fibronectin and macrophages of MEL cells and primary fetal liver erythroblasts. The avidity of MEL cells for purified mouse fibronectin was greater than that of the primary cells. In addition, we have shown that MEL cells carry ligands/counter-receptors for sialoadhesin (Sn) and the erythroblast receptor (EbR), two hemagglutinins expressed by hematopoietic stromal macrophages. These two macrophage-binding activities were independent of erythroid fibronectin-binding activity. Proteolysis of MEL cell surface receptors was necessary to reveal these activities, with this process providing a means for using MEL cells as ligand cells in studies of macrophage hemagglutinins. While erythroid adhesion to fibronectin and components of the extracellular matrix may be of importance in early erythropoiesis, hemagglutinin-expressing stromal macrophages provide the appropriate microenvironmental niche for the terminal stages of erythropoiesis preceding the release of enucleated cells into the circulation.