15‐Deoxy‐Δ12,14‐prostaglandin J2 (15d‐PGJ2) was initially identified as a high affinity natural ligand for the peroxisome proliferator‐activated receptor (PPAR)‐γ. Recent studies have shown that it has a potent anti‐inflammatory effect by attenuating the expression of proinflammatory mediators in activated macrophages, mainly through the inhibition of nuclear factor (NF)‐κB‐dependent transcription of inflammatory genes. In this study, we investigated the synergistic effect of 15d‐PGJ2 on the expression of LPS‐induced chemokine KC mRNA in mouse peritoneal macrophages. The time course of KC mRNA expression in cells stimulated with 15d‐PGJ2 plus LPS simultaneously (15d‐PGJ2/LPS) showed similar patterns to the cells treated with LPS alone, and 15d‐PGJ2 had no effect on the stability of LPS‐induced KC mRNA expression. Although NF‐κB activity in cells treated with LPS was augmented by 15d‐PGJ2, pyrrolidone dithiocarbamate (PDTC) did not block the synergistic effect of 15d‐PGJ2 on LPS‐induced KC mRNA expression. However, the synergistic effect of 15d‐PGJ2 was markedly inhibited when the macrophages were treated with a inhibitor of the mitogen‐activated protein kinase (MAPK) signalling pathway, 2′‐amino‐3′‐methoxyflavine (PD98059). Therefore, the mechanism of synergistic action of 15d‐PGJ2 on the expression of LPS‐induced KC mRNA in mouse peritoneal macrophages is possibly related to the MAPK signalling pathway, not to NF‐κB activation. These data may contribute to unravelling some of the different mechanisms contrary to the anti‐inflammatory effect of 15d‐PGJ2.