The hepatic carbohydrate-recognizing asialoglycoprotein receptor (ASGR1) mediates the endocytosis/lysosomal degradation of desialylated glycoproteins following binding to terminal galactose/N-acetylgalactosamine. Human heterozygote-carriers of ASGR1-deletions exhibited ~34% lower risk of coronary artery disease and ~10-14% non-HDL-cholesterol reduction. Since PCSK9 is a major degrader of LDLR, we examined the regulation of LDLR and/or PCSK9 by ASGR1. We investigated the role of endogenous/overexpressed ASGR1 on LDLR degradation and functionality in nave HepG2 and HepG2-PCSK9-knockout cells by Western-blot and immunofluorescence. ASGR1, like PCSK9, targets LDLR and both interact with/enhance the degradation of the receptor independently. The lack of cooperativity between PCSK9 and ASGR1 on LDLR expression was confirmed in livers of wild-type (WT) versus Pcsk9-/- mice. ASGR1-knockdown in nave HepG2 cells significantly increased total (~1.2-fold) and cell-surface (~4-fold) LDLR protein. In HepG2-PCSK9-knockout cells ASGR1-silencing led to ~2-fold higher levels of LDLR protein and DiI-LDL uptake associated with ~4-fold increased cell-surface LDLR. Overexpression of WT-ASGR1 reduced primarily the immature non-O-glycosylated LDLR (~110 kDa), whereas the triple Gln240/Trp244/Glu253 Ala-mutant (loss of carbohydrate-binding) reduced the mature form of the LDLR (~150 kDa), suggesting that ASGR1 binds the LDLR in sugar-dependent and -independent fashion. Furin sheds ASGR1 at RKMK103 into a secreted form, likely resulting in a loss-of-function on LDLR. LDLR is the first example of a liver-receptor ligand of ASGR1. Additionally, we demonstrate that lack of ASGR1 enhances LDLR levels and DiI-LDL incorporation, independently of PCSK9. Overall, silencing of ASGR1 and PCSK9 may lead to higher LDL-uptake by hepatocytes, thereby providing a novel approach to further reduce LDL-cholesterol.