Scavenger receptors (ScRs) are a structurally unrelated family of receptors with the ability to bind modified low density lipoprotein (LDL) as well as a broad range of polyanionic ligands. CD68, whose expression is restricted to mononuclear phagocytes, is a unique ScR family member, owing to its lysosome associated membrane protein (LAMP)-like domain and predominant endosomal distribution. Knockout (ko) mice were generated to directly evaluate the role murine CD68 may play in oxidized LDL (Ox-LDL) uptake. However, CD68⁻/⁻ macrophages took up Ox-LDL robustly. Likewise, no defects were observed in the ability of CD68⁻/⁻ mononuclear phagocytes to take up or mount an effective innate response against a number of microbes. Curiously, CD68⁻/⁻ mononuclear phagocytes exhibited a trend toward enhanced antigen presentation to CD4⁺ T-cells, raising the possibility that CD68 may function either to negatively regulate antigen uptake, loading, or major histocompatibility complex class II (MHC-II) trafficking.