The macrophage mannose receptor (MR) has an established role in the phagocytosis of a wide range of microbes, and also functions in viral endocytosis, and clearance of a number of endogenous glycoproteins from the circulation. Its broad ligand specificity is mediated by tandemly linked carbohydrate recognition domains (CRDs). Recent studies suggest that binding or internalization of both natural and synthetic ligands of MR CRDs may modulate macrophage (MPhi ) function, for example to increase cidal capacity or cytokine synthesis. To identify endogenous ligands in the normal mouse we used an Fc-fusion protein (CRD4-7Fc) bearing four of the CRDs of MR. CRD4-7Fc recognized endocytic compartments of cultured MPhi, consistent with lysosomal enzymes being major ligands of MR. CRD4-7Fc also recognized MPhi and some endothelial cells in tissues, and intensely labeled secretory cells of the exocrine pancreas, salivary gland and thyroid. Strongly MR-positive interstitial cells were found in close proximity to the ligand-rich secretory cells, suggesting a role for MR in uptake of secretory glycoproteins, including thyroglobulin which was identified as a novel ligand in vitro. Endocytosis of these ligands by MR may have implications for tissue homeostasis and immunity, including antigen presentation, in secretory organs.