Liver X Receptor (LXR) is a potential drug target for atherosclerosis. One of the major challenges in taking LXR modulators to the clinic is steatosis. It was reported that sterol LXR agonists selectively activate LXR in the intestine and macrophage cells rather than in the liver. We hypothesize that sterol LXR agonists may selectively inhibit atherosclerosis without causing hepatic lipogenesis. Thus, based on LXR structure, 12 sterol compounds were designed and tested in a dual-luciferase reporter gene experiment. It was confirmed that compounds 4 and 6 were LXR agonists. Further experiments demonstrated that compounds 4 and 6 inhibit the formation of macrophage foam cells without inducing triglyceride accumulation in either hepatocytes or adipocytes. In vivo studies demonstrated that compound 4 promotes reverse cholesterol transport without inducing hepatic lipogenesis. Thus, we report that these compounds with sterol scaffolds can be promising leads for the treatment of atherosclerosis without inducing steatosis.