Natural and synthetic agonists of the peroxisome proliferator-activated receptor γ (PPARγ) regulate adipocyte differentiation, glucose homeostasis, and inflammatory responses. Although effects on adipogenesis and glucose metabolism are genetically linked to PPARγ, the PPARγ dependence of antiinflammatory responses of these substances is less clear. Here, we have used a combination of mRNA expression profiling and conditional disruption of the PPARγ gene in mice to characterize programs of transcriptional activation and repression by PPARγ agonists in elicited peritoneal macrophages. Natural and synthetic PPARγ agonists, including the thiazolidinedione rosiglitazone (Ro), modestly induced the expression of a surprisingly small number of genes, several of which were also induced by a specific PPARδ agonist. The majority of these genes encode proteins involved in lipid homeostasis. In contrast, Ro inhibited induction of broad subsets of lipopolysaccharide and IFN-γ target genes in a gene-specific and PPARγ-dependent manner. At high concentrations, Ro inhibited induction of lipopolysaccharide target genes in PPARγ-deficient macrophages, at least in part by activating PPARδ. These studies establish overlapping transactivation and transrepression functions of PPARγ and PPARδ in macrophages and suggest that a major transcriptional role of PPARγ is negative regulation of specific subsets of genes that are activated by T helper 1 cytokines and pathogenic molecules that signal through pattern recognition receptors. These findings support a physiological role of PPARγ in regulating both native and acquired immune responses.