LDL-receptor (LDLR)-mediated uptake of LDL-C into hepatocytes is impaired by lysosomal degradation of LDLR, which is promoted by proprotein convertase subtilisin/kexin type 9 (PCSK9). Cell surface binding of PCSK9 to LDLR produces a complex that translocates to an endosome, where the acidic pH strengthens the binding affinity of PCSK9 to LDLR, preventing LDLR recycling to the cell membrane. We present a new approach to inhibit PCSK9-mediated LDLR degradation, namely, targeting the PCSK9/LDLR interface with a PCSK9-antagonist, designated Flag-PCSK9PH, which prevents access of WT PCSK9 to LDLR. In HepG2 cells, Flag-PCSK9PH, a truncated version (residues 53-451) of human WT PCSK9, strongly bound LDLR at the neutral pH of the cell surface but dissociated from it in the endosome (acidic pH), allowing LDLR to exit the lysosomes intact and recycle to the cell membrane. Flag-PCSK9PH thus significantly enhanced cell-surface LDLR levels and the ability of LDLR to take up extracellular LDL-C.