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Background Recent evidence suggested that ClC-3, encoding Cl − channel or Cl − /H + antiporter, plays a critical role in regulation of a variety of physiological functions. However, remarkably little is known about whether ClC-3 is involved in atherosclerosis. This study aims to establish the involvement and direct role of ClC-3 in atherogenesis and underlying mechanisms by using ClC-3 and ApoE double null mice. Methods and results After a 16-week western-type high-fat diet, the ClC-3 +/+ ApoE −/− mice developed widespread atherosclerotic lesions in aorta. However, the lesion size was significantly reduced in aorta of ClC-3 −/− ApoE −/− mice. Compared with the ClC-3 +/+ controls, there was significantly decreased ox-LDL binding and uptake in isolated peritoneal macrophages from ClC-3 −/− mice. Moreover, the expression of scavenger receptor SR-A, but not CD36, was significantly decreased in both ClC-3 −/− peritoneal macrophages and aortic lesions from ClC-3 −/− ApoE −/− mice. These findings were further confirmed in ox-LDL-treated RAW264.7 macrophages, which showed that silence of ClC-3 inhibited SR-A expression, ox-LDL accumulation and foam cell formation, whereas overexpression of ClC-3 produced the opposite effects. In addition, ClC-3 siRNA significantly inhibited, whereas ClC-3 overexpression increased, the phosphorylation of JNK/p38 MAPK in ox-LDL-treated RAW264.7 foam cells. Pretreatment with JNK or p38 inhibitor abolished ClC-3-induced increase in SR-A expression and ox-LDL uptake. Finally, the increased JNK/p38 phosphorylation and SR-A expression induced by ClC-3 could be mimicked by reduction of [Cl − ] i by low Cl − solution. Conclusions Our findings demonstrated that ClC-3 deficiency inhibits atherosclerotic lesion development, possibly via suppression of JNK/p38 MAPK dependent SR-A expression and foam cell formation. [ABSTRACT FROM AUTHOR]