BACKGROUND: Oxidized low-density lipoprotein (LDL) is associated with cardiovascular disease. Macrophages contribute to LDL oxidation, and oxidized LDL (oxLDL) affects macrophage function. We searched for the strongest gene correlates of oxLDL in macrophages in coronary plaques and studied the effect of oxLDL on their expression in THP-1 cells. METHODS AND RESULTS: Gene expression in macrophages isolated from coronary plaque macrophages from hypercholesterolemic swine was measured on Agilent Human cDNA microarrays. Compared with a universal reference, 1653 transcripts were deregulated. The expression of 11 genes correlated positively and the expression of 5 genes correlated negatively with plaque oxLDL. Interferon regulatory factor-1 (IRF1; R2 = 0.69) and toll-like receptor 2 (TLR2; R2 = 0.18) were the strongest positive correlates of oxLDL. Superoxide dismutase 1 (SOD1) was the strongest inverse correlate of oxLDL (R2 = 0.57). Immunohistochemical analysis showed colocalization of IRF1, TLR2, and SOD1 protein in macrophages and confirmed the RNA expression data. OxLDL-induced foam cell formation in THP-1 macrophages was associated with increased expression of IRF1 and TLR2 and decreased expression of SOD1. CONCLUSIONS: Our data support the hypothesis that oxLDL is a proinflammatory stimulus that induces the expression of TLR2 and IRF1, 2 important gene regulators of innate immune response, and inhibits the expression of the antioxidant SOD1.