There is increasing evidence that the ligation of adhesion molecules such as L-selectin can activate phagocytes to their full inflammatory potential. Sulfatide has been established as ligand for L-selectin and shown to trigger intracellular signals in human neutrophils. However, it remains unclear whether the ligation of L-selectin with sulfatide affects neutrophil phagocytosis. We studied the effects of sulfatide upon Fc gamma R- and CR3-mediated human neutrophil phagocytosis. Adhesion of the cells to a sulfatide-coated surface resulted in a dose-dependent enhancement of phagocytosis mediated via Fc gamma R or CR3, or both receptors. Galactocerebroside, but not glucocerebroside, also enhanced phagocytosis by neutrophils; therefore, galactose residue is thought to be required on ceramide molecules for the activation. Chymotrypsin-treated neutrophils, from which most L-selectin had been removed, reacted with sulfatide and galactocerebroside to enhance phagocytosis. These results suggest that an unidentified receptor for these cerebrosides exists on neutrophils and participates in the enhancement of phagocytosis.