Aim To investigate the effect of coiled-coil domain containing protein 80 (CCDC80) on the expression of inflammatory factors in THP-1 macrophage-derived foam cells and related molecular mechanisms. Methods THP-1 cells were treated with phorbol ester (160 nmol/L) to induce the cells to differentiate into macrophages, and then treated with oxidized low density lipoprotein (50 mg/L) to form foam cell, performing conventional cell culture in vitro. The expression of interleukin-1β(IL-1β), interleukin-6(IL-6), tumor necrosis factor-α(TNF-α) and monocyte chemoattractant protein-1(MCP-1) was detected by ELISA, the expression of Toll like report 4(TLR4), lipoprotein lipase(LPL) and nuclear factor-κB(NF-κB) was detected by real-time PCR and Western blot. Foam cells were treated with TLR4 siRNA and LPL siRNA, and the effects of CCDC80 on the expression of TLR4, LPL, NF-κB and p-NF-κB in foam cells were detected by fluorescence quantitative PCR and Western blot. Results CCDC80 significantly increased THP-1 macrophage-derived foam cell inflammatory factor secretion and p-NF-κB expression. After TLR4 siRNA treated foam cells, the expression of TLR4, LPL and p-NF-κB reduced significantly. After LPL siRNA treated foam cells, the expression of LPL and p-NF-κB decreased significantly. Conclusion CCDC80 promotes the activation of NF-κB signaling pathway through the TLR4/LPL pathway, thereby increasing the secretion of IL-1β, IL-6, TNF-α and MCP-1.