The marginal zone macrophages of the spleen are implicated in the clearance of polysaccharides, but underlying mechanisms need to be pinpointed. SIGN‐R1 is one of five recently identified mouse genes that are homologous to human DC‐SIGN and encode a single, external, C‐terminal C‐type lectin domain. We find that a polyclonal antibody to a specific SIGN‐R1 peptide reacts primarily and strongly with a subset of macrophages in the marginal zone of spleen and lymph node medulla. In both sites, SIGN‐R1 exists primarily in an aggregated form, resistant to dissociation into monomers upon boiling in SDS under reducing conditions. Upon transfection into three different cell lines, high‐mol.‐wt forms bearing SIGN‐R1 are expressed, as well as reactivity with ER‐TR9, a mAb previously described to react selectively with marginal zone macrophages. SIGN‐R1‐expressing macrophages preferentially sequester dextrans following i.v. injection. Likewise, when phagocytic cells are enriched from spleen and tested in culture, dextran is selectively endocytosed by a subset of very large SIGN‐R1⁺ cells representing ∼5% of total released macrophages. Uptake of FITC–dextran by these macrophages in vivo and in vitro is blocked by ER‐TR9 and polyclonal anti‐SIGN‐R1 antibodies. Following transfection with SIGN‐R1, cell lines become competent to endocytose dextrans. The dextran localizes primarily to compartments lacking transferrin receptor and the LAMP‐1 CD107a panlysosomal antigen. Therefore, SIGN‐R1 mediates the uptake of dextran polysaccharides, and it is predominantly expressed in the macrophages of the splenic marginal zone and lymph node medulla.