The transcription factor NF-B p65 is a key regulator in the regulation of an inflammatory response and in the pathology of atherosclerosis. However, there is no direct evidence for the role of NF-B in macrophages in the development of atherosclerosis. We investigated whether macrophage overexpression of p65 in ApoE knockout mice could improve atherosclerosis. Transgenic mice overexpressing p65 in macrophages (TG) were generated by crossing fatty acid binding protein 4 (aP2) promoter-controlled p65 mice with ApoE knockout (KO) mice. TG mice exhibited functional activation of NF-B signaling in macrophages and fat tissues. We observed that the atherosclerotic lesion was 40% less in the TG mice compared with the ApoE KO controls fed with a standard atherogenic diet for 16 weeks (N = 12). The TG mice were leaner from reduced fat mass by increased energy expenditure. Moreover, the overexpression of p65 in macrophages suppressed foam cell formation. Our results show that there are 1) an increased fatty acid oxidation in macrophages, 2) a reduced scavenger receptor CD36 expression and lipid accumulation in microphages, 3) reduced inflammation cytokines in serum, and 4) enhanced energy expenditure in TG mice. Our data suggest that activation of NF-B in macrophages has atheroprotective effects in mice by enhancing lipid metabolism and energy expenditure.