To explore whether Daxx mediates oxidized low-density lipoprotein (Ox-LDL)-induced cholesterol accumulation and apopotosis in macrophage and the underlying molecular mechanisms, intracellular lipid droplets and lipid levels were assayed by oil red O staining and high performance liquid chromatography (HPLC), respectively, the apoptotic effect of RAW264.7 cells induced by Ox-LDL was analyzed by flow cytometric analysis and acridine orange/ethidium bromide (AO/EB) staining, the mRNA expressions of Daxx was quantified by Real time RT- PCR, the protein expression of caveolin-1 was detected by Western-blotting, Daxx-specific small interfering RNA(Daxx siRNA) was transfected to RAW264.7 cell by lipofectamin. Ox-LDL up-regulated the expression of Daxx mRNA, increased the accumulation of intercellular cholesterol in RAW264.7 macrophages, and induced the apoptosis of RAW264.7 macrophages. However, Ox-LDL-induced intercellular cholesterol accumulation and apoptosis in RAW264.7 cells was prevented by Daxx siRNA. Ox-LDL also induced caveolin-1 expression and this effect is significantly suppressed by Daxx siRNA. It can be concluded that Daxx mediates Ox-LDL-induced cholesterol accumulation and apoptosis in macrophages by up-regulating caveolin-1 expression. These findings provide an important demonstration that Daxx might be associated with the development of atherosclerosis.