Human myelogenous leukemic cell lines, U-937, ML-1, and THP-1, were induced to differentiate into maturing macrophage-like cells upon treatment with any glycophorins from either human, monkey or cow erythrocyte membrane. The differentiated cells expressed lower growth potential, and higher nitroblue tetrazolium-reducing activity, Fc-receptor, phagocytic activity and non-specific esterase activity. The differentiation-inducing activities of the glycophorins were significantly reduced after neuraminidase treatment. On the other hand, sialic acid and colominic acid (a polymer of sialic acid) were inactive. These results suggest that some conformational requirement involving the linkage of sialic acid residues in the glycoproteins is necessary for the observed differentiation-inducing activity.