The high-cholesterol/high-fat Western diet has abetted an epidemic of atherosclerotic cardiovascular disease, the leading cause of death in industrialized nations. Liver X receptors (LXRs) are oxysterol sensors that are required for normal cholesterol and triglyceride homeostasis, yet synthetic LXR agonists produce undesirable hypertriglyceridemia. Here we report a previously unrecognized role for hepatic LXRalpha in the links between diet, serum lipids, and atherosclerosis. A modest increase in hepatic LXRalpha worsened serum lipid profiles in LDL-receptor null mice fed normal chow but had the opposite effect on lipids and afforded strong protection against atherosclerosis on a Western diet. The beneficial effect of hepatic LXRalpha was abrogated by a synthetic LXR agonist, which activated SREBP-1c and its target genes. Thus, the interplay between diet and hepatic LXRalpha is a critical determinant of serum lipid profiles and cardiovascular risk, and selective modulation of LXR target genes in liver can ameliorate hyperlipidemia and cardiovascular disease.