15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is an endogenous peroxisome proliferator-activated receptor γ (PPARγ) agonist that suppresses progressive matrix deposition; however, little is known about the effects of 15d-PGJ2 on human peritoneal mesothelial cells (HPMCs). We investigated the following: (i) the expression of PPARγ; (ii) the effect of 15d-PGJ2 on angiotensin II (Ang II)-induced fibronectin (FN) expression and secretion; (iii) the effect of 15d-PGJ2 (with or without Ang II and with or without the specific PPARγ antagonist GW9662) and pioglitazone, a synthetic PPARγ agonist, on hepatocyte growth factor (HGF) expression and secretion; (iv) the effect of HGF on Ang II-induced FN expression and secretion; (v) the expression of c-Met (a specific HGF receptor) and its phospho-signal; and (vi) the involvement of HGF in the effect produced by 15d-PGJ2 using selective c-Met inhibitor PHA-665752. The presence of PPARγ was detected by western blot analysis. 15d-PGJ2 inhibited Ang II-induced FN expression and increased HGF expression, even in the presence of Ang II. This effect of HGF expression was completely prevented by co-treatment with GW9662. Additionally, upregulation of HGF secretion induced by 15d-PGJ2 and HGF production induced by pioglitazone was revealed. We demonstrated the presence of c-Met, and presented evidence that HGF inhibits Ang II-induced FN expression and activates phosphorylation of c-Met, which is blocked by PHA-665752; 15d-PGJ2 also activated c-Met phosphorylation. Furthermore, PHA-665752 attenuates the inhibitory effects of 15d-PGJ2 on FN secretion. These findings suggest that 15d-PGJ2 has a novel and potent antifibrotic effect in HPMC and this action is likely mediated by HGF.