Peroxisome proliferator-activated receptor-γ (PPARγ) and liver X receptor-α (LXRα) are nuclear ligand-activated transcription factors, which regulate lipid metabolism and inflammation. Murine J774.2 macrophages were stimulated with Escherichia coli lipopolysaccharide (concentration, 10 μg/mL) with or without the PPARγ ligand, 15-deoxy-Δ12,14 prostaglandin J2 (15d-PGJ2), or the LXRα ligands, 22(R)-hydroxycholesterol and T0901317 (concentration range, 0.01-10 μmol/L), alone or in combination. Nitric oxide (NO) metabolites and tumor necrosis factor α production, inducible NO synthase expression, and mitochondrial respiration were measured. When added to the cells as single agents, 15d-PGJ2, 22(R)-hydroxycholesterol, or T0901317 reduced the lipopolysaccharide-induced NO and tumor necrosis factor α production and the inducible NO synthase expression, and partially maintained mitochondrial respiration in a concentration-dependent manner. When added to the cells in combination at suboptimal concentrations, 15d-PGJ2 with 22(R)-hydroxycholesterol, or 15d-PGJ2 with T0901317, exerted anti-inflammatory effects similar to much higher concentrations (10,000-fold to 100,000-fold) of each ligand alone. The anti-inflammatory effects of these ligands, alone or in combination, were associated with reduction of nuclear factor-κB activation and with enhancement of PPARγ DNA binding. LXRα expression was upregulated in response to 15d-PGJ2 and to the LXRα ligands when added alone or in combination. Immunoprecipitation experiments revealed that PPARγ interacted with LXRα. Our data demonstrate that the PPARγ ligand, 15d-PGJ2, and the LXRα ligands, 22(R)-hydroxycholesterol and T0901317, although binding to different nuclear receptors (i.e., PPARγ and LXRα, respectively), affect mediator production through common cell signaling events and exert a synergistic potentiation in a combined treatment at suboptimal concentrations. Thus, our data suggest that PPARγ and LXRα may interact in controlling the inflammatory response in macrophages.