In the spleen, the MZ forms an interface between red and white pulp. Its major function is to trap blood-borne antigens and to reorient them to APCs and lymphocytes. SIGN-R1⁺ cells are of the MZ inherent cell population, which for a long time, have been considered as macrophages. We now show that one subpopulation of SIGN-R1⁺ cells that express MHC II molecules should be considered as a resident DC. Histological analysis indicated that SIGN-R1⁺ cells have dendritic-like protrusions extending into T and B cell areas. Flow cytometry analysis revealed an expression profile of adhesion, costimulatory, and MHC molecules similar to cDCs but distinct from macrophages. Most importantly, SIGN-R1⁺MHC⁺ cells were able to present antigen to naïve CD4 T cells, as well as to cross-present soluble, particulate antigens secreted by Listeria monocytogenes to CD8 T cells in vitro and in vivo. Our experiments identified SIGN-R1⁺MHC II⁺ cells as professional APCs and indicate their nature as splenic resident DCs.