The role of adhesion molecules in antibody-dependent cell-mediated cytotoxicity (ADCC) of macrophages toward the extracellular parasite Schistosoma mansoni was investigated by using 1) a panel of blocking mAbs directed against adhesion molecules and 2) different soluble ligands as candidate inhibitors of ADCC. The results show that the beta2-integrin Mac-1 (CD11b/CD18), L-selectin (CD62-L), and the carbohydrate determinant sialyl Lewis(x) (sLe(x); sCD15) are required for macrophage effector function toward schistosomula targets. On the other hand, the parasite counter-receptors involved in ADCC were found to share common motifs with the mammalian selectin-carbohydrate families. One family of parasite receptor(s) involved in ADCC carries the Lewis(x) (Le(x); CD15) carbohydrate structure, whereas a second family of receptor(s) appears to display selectin-like properties with affinity for the sLe(x) tetrasaccharide. Immunostaining experiments confirmed that schistosomula express on their surface hostlike molecules recognized by anti-Le(x) (CD15) and by anti-human E-selectin (CD62-E) mAbs. The double receptor-ligand interaction between macrophages and parasite targets provides new insights into the biologic roles of selectins and Le(x)-related structures in immunity against helminthic parasites.