Macrophage-derived foam cells in atherosclerotic lesions are generally thought to play a major role in the pathology of the disease. Because macrophages play a central role in the inflammatory response, and the atherosclerotic lesion has features associated with chronic inflammatory settings, we investigated foam cell inflammatory potential. THP-1 derived macrophages were treated with oxidized LDL (OxLDL) for 3 days to lipid load the macrophages and establish a foam cell-like phenotype. The cells were then activated by treatment with lipopolysacharide (LPS) and RNA was harvested at 0, 1 and 6 hrs post LPS addition. RNA from treated and control cells was hybridized to microarrays containing approximately 16000 human cDNAs. Genes that exhibited a 4-fold or greater increase or decrease at either 1 or 6 hrs after LPS treatment were counted as LPS responsive genes. Employing these criteria, 127 LPS responsive genes were identified. Prior treatment of THP-1 macrophages with OxLDL affected the expression of 57 of these 127 genes. Among these 57 were a group of chemokine, cytokine, and signal transduction genes with pronounced expression changes. OxLDL pre-treatment resulted in a signficiant perturbation of LPS induced NFKB activation. Furthermore, some of the OxLDL effects appear to be mediated by the nuclear receptors RXR and PPAR gamma, as pre-treatment of THP-1 macrophages with ligands for these receptors, followed by LPS treatment, recapitulates the OxLDL plus LPS results for several of the most significantly modulated genes.