A peroxisome proliferator‐activated receptor γ (PPARγ) ligand, 15‐deoxy‐Δ12,14‐prostaglandin J2 (15d‐PGJ2), has been reported to possess anti‐inflammatory activity in activated monocytes/macrophages. In this study, we investigated the effect of 15d‐PGJ2 on the lipopolysaccharide (LPS)‐induced expression of chemokine mRNAs, especially macrophage inhibitory protein (MIP)‐2 (CXCL2), in mouse peritoneal macrophages. The inhibitory actions of the natural PPARγ ligands, 15d‐PGJ2 and prostaglandin A1 (PGA1), on the expression of RANTES (regulated upon activation, normal T expressed and secreted; CCL5), MIP‐1β (CCL4), MIP‐1α (CCL3), IFN‐γ‐inducible protein 10 kilodaltons (IP‐10; CXCL10) and monocyte chemoattractant protein‐1 (MCP‐1; CCL2) mRNA in LPS‐treated cells were stronger than those of the synthetic PPARγ ligands troglitazone and ciglitazone. However, 15d‐PGJ2 enhanced the expression of LPS‐induced MIP‐2 (CXCL2) mRNA. A specific PPARγ antagonist (GW9662) had no effect on the inhibitory action of 15d‐PGJ2 and PGA1 in LPS‐induced chemokine mRNA expression and on the synergistic action of 15d‐PGJ2 in LPS‐induced MIP‐2 (CXCL2) expression. Moreover, LPS itself reduced the expression of PPARγ. Although the synergistic effect of 15d‐PGJ2 on LPS‐induced MIP‐2 (CXCL2) mRNA expression was remarkable, the production of MIP‐2 (CXCL2) in cells treated with 15d‐PGJ2 and LPS did not increase compared to the production in cells treated with LPS alone. The synergistic action of 15d‐PGJ2 on LPS‐induced MIP‐2 (CXCL2) mRNA expression was dependent on the activation of nuclear factor‐κB (NF‐κB), and 15d‐PGJ2 increased the phosphorylation of p38 and stress‐activated protein kinase/c‐Jun N‐terminal kinase (SAPK/JNK) in cells stimulated with LPS. These results suggest that the synergistic effect of 15d‐PGJ2 on LPS‐induced MIP‐2 (CXCL2) expression is PPARγ‐independent, and is mediated by the p38 and SAPK/JNK pathway in mitogen‐activated protein kinase signaling pathways, which activates NF‐κB. Our data may give more insights into the different mechanisms contrary to the anti‐inflammatory effect of 15d‐PGJ2 on the expression of chemokine genes.