Aim To investigate the relationship between apolipoprotein E (ApoE) receptor 2 (ApoER2) degradation by proprotein convertase subtilisin kexin 9 (PCSK9) and the anti-inflammatory effect of ApoE/ApoER2. Methods Human umbilical vein endothelial cells (HUVEC) and HepG2 cells were cultured in vitro, Western blot and ELISA were used to detect the effects of lipopolysaccharide (LPS) on the expression and secretion of Toll-like receptor (TLR4), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and PCSK9 in HUVEC; the effects of ApoE3 on the expression and secretion of TNF-α, IL-6, PCSK9 and ApoER2 in HUVEC induced by LPS; the effects of three isoforms of ApoE (ApoE2, ApoE3 and ApoE4) on the expression of PCSK9 and ApoER2 in HUVEC and HepG2 cells under non-inflammatory conditions; and the effects of PCSK9 on the expression and secretion of ApoER2, TNF-α and IL-6 in HUVEC. Results Western blot and ELISA showed that LPS up-regulated the expression and secretion of TLR4, TNF-α, IL-6 and PCSK9 in HUVEC; ApoE3 inhibited LPS-induced inflammatory responses, and up-regulated ApoER2 expression and secretion; the three isoforms of ApoE (ApoE2, ApoE3 and ApoE4) had no effect on the expression of PCSK9 and ApoER2 in HUVEC and HepG2 cells under non-inflammatory conditions. Different doses (0,0.5,1.0 and 2.5 mg/L) of recombinant human PCSK9 were used to treat HUVEC for 24 h, Western blot and ELISA showed that PCSK9 up-regulated the expression and secretion of TNF-α and IL-6, and down-regulated the expression of ApoER2. Conclusion PCSK9 antagonizes the anti-inflammatory effects of ApoE/ApoER2 by degrading ApoER2.