Aim To explore whether nuclear factor kappa B (NF-κB) manipulates Sortilin expression to regulate lipid metabolisms and foam cell formation of lipid-laden THP-1 macrophage. Methods The levels of Sortilin mRNA and protein were detected by quantitative real-time PCR (qRT-PCR) and Western blot in lipid-laden THP-1 macrophage incubated with NF-κB activator phorbol-12-myristate-13-acetate (PMA) or its specific inhibitor ammonium pyrrolidinedithiocarbamate (PDTC). Under the lipid-laden THP-1 macrophage treated with Sortilin shRNA and together with PMA, cholesterol efflux from macrophage was measured by liquid scintillation counting apparatus, intracellular lipid contents were detected by high performance liquid chromatography, and the intracellular lipid droplets were stained with oil red O. Results PMA treatment increased the levels of Sortilin mRNA and protein in lipid-laden THP-1 macrophage, whereas PDTC incubation decreased macrophage Sortilin expression. When lipid-laden THP-1 macrophage was treated with PMA alone, the cholesterol efflux of macrophages was reduced, the intracellular lipid accumulation was increased, and foam cell formation was increased. Reversely, the cholesterol efflux of lipid-laden macrophage was increased, the intracellular lipid accumulation was decreased, and foam cell formation was reduced under the treatment with Sortilin shRNA and supplemented with PMA. Conclusion NF-κB promotes Sortilin expression to inhibit the cholesterol efflux from lipid-laden macrophage and accelerates the accumulation of intracellular lipid and the formation of foam cell.