Schistosoma mansoni soluble egg antigens (SEAs) are crucially involved in modulating the host immune response to infection by S. mansoni. We report that human dendritic cells bind SEAs through the C-type lectin dendritic cell–specific ICAM-3-grabbing nonintegrin (DC-SIGN). Monoclonal antibodies against the carbohydrate antigens Lewis^x (Le^x) and GalNAcβ1-4(Fucα1-3)GlcNAc (LDNF) inhibit binding of DC-SIGN to SEAs, suggesting that these glycan antigens may be critically involved in binding. In a solid-phase adhesion assay, DC-SIGN-Fc binds polyvalent neoglycoconjugates that contain the Le^x antigen, whereas no binding was observed to Galβ1-4GlcNAc, and binding to neoglycoconjugates containing only α-fucose or oligosaccharides with a terminal α1-2-linked fucose is low. These data indicate that binding of DC-SIGN to Le^x antigen is fucose-dependent and that adjacent monosaccharides and/or the anomeric linkage of the fucose are important for binding activity. Previous studies have shown that DC-SIGN binds HIV gp120 that contains high-mannose-type N-glycans. Site-directed mutagenesis within the carbohydrate recognition domain (CRD) of DC-SIGN demonstrates that amino acids E³²⁴ and E³⁴⁷ are involved in binding to HIV gp120, Le^x, and SEAs. By contrast, mutation of amino acid Val³⁵¹ abrogates binding to SEAs and Le^x but not HIV gp120. These data suggest that DC-SIGN recognizes these ligands through different (but overlapping) regions within its CRD. Our data imply that DC-SIGN not only is a pathogen receptor for HIV gp120 but may also function in pathogen recognition by interaction with the carbohydrate antigens Le^x and possibly LDNF, which are found on important human pathogens, such as schistosomes and the bacterium Helicobacter pylori.