Diet-induced changes in serum lipoproteins are a major risk factor for the development of atherosclerosis, the leading cause of mortality in Westernized countries. Atherosclerosis is now appreciated to be a systemic inflammatory disease where increased synthesis of inducible proteins by the liver, such as C-reactive protein (CRP) and others, may play roles in accelerating the disease process. To systematically investigate the genetic response of the liver to diet-induced atherosclerosis, we applied high-density microarray technology in a mouse model of atherosclerosis (LDLR-/- mouse). LDLR-/- mice and congenic (LDLR+/+) controls were placed on low-fat (LF) or high-fat (HF) Western-style diets. The Western diet produced sustained elevations in total cholesterol (2.5-fold for LDLR+/+, 5.0-fold LDLR-/-) relative to the respective LF groups. Tissues were harvested after 12 wk when significant atherosclerotic lesion development was first detectable by en face histomorphometry of oil red O-stained aortas. Diet, rather than genotype, was most highly associated with development of atherosclerotic lesions. Liver mRNA expression profiles of triplicate animals from each group were determined by high-density oligonucleotide microarrays; and genes with transcript levels influenced by genotype and diet were identified by two-way ANOVA. Approximately one-third of the 102 genes identified to be altered by diet [Pr(F) < 0.0005] were involved in lipid metabolism. In addition, we identified components of the alternative complement pathway, including C3, properdin, and factor D, for which mRNA levels were independently confirmed by quantitative real-time RT-PCR analysis, and C3 protein was demonstrated in aortic lesions by immunostaining. These findings suggest that induction of the alternative complement pathway may be an additional mechanism by which a high-fat/Western diet accelerates atherosclerosis.