Liver cells absorb apolipoprotein (Apo) B48-carrying lipoproteins in ApoE's absence, albeit not as efficiently as the ApoE-mediated process. Our objective was to identify differentially expressed hepatic endosome proteins in mice expressing ApoB48 but lacking ApoE and ApoB100 expression (ApoE-/-/B48/48). We purified early and late endosomes from ApoE-/-/B48/48 and wild-type mouse's livers. In ApoE-/-/B48/48 mouse's hepatic endosomes, proteomic analysis revealed elevated protein levels of major urinary protein 6 (MUP), calreticulin, protein disulfide isomerases (PDI) A1, and A3. These proteins are capable of interacting with lipids/lipoproteins and triggering receptormediated endocytosis. In addition, hepatic endosomes from ApoE-/- /B48/48 mice exhibited significantly reduced protein levels of haptoglobin, hemopexin, late endosome/lysosome interacting protein, cell division control protein 2 homolog, γ-soluble Nethylmaleimide- sensitive factor attachment protein, vacuolar ATP synthase catalytic subunit A1, dipeptidyl peptidases II, cathepsin B, D, H, and Z. These proteins participate in plasma heme clearance, receptor-mediated signaling, membrane fusion, endosomal/lysosomal acidification, and protein degradation. The significance of increasing endosomal MUP, calreticulin and PDIs in ApoE-/-/B48/48 mouse liver cells is not clear; however, reducing endosomal/ lysosomal membrane proteins and hydrolases might be, at least partially, responsible for the retarded clearance of plasma ApoB-carrying lipoproteins in ApoE-/-/B48/48 mice.