Relaxin (RLX) has antifibrotic effects in a number of tissues. Many of these effects are similar to those induced by the activators of peroxisome proliferator-activated receptor gamma (PPARγ), raising the possibility that a mechanism for RLX's antifibrotic effects may involve activation of the PPARγ pathway. This study investigated the effect of RLX on PPARs and their mechanism of upregulation. It shows that RLX stimulates ligand-independent PPAR activation in a dose-dependent manner. The combined effect of RLX and PPARγ agonists was superadditive, suggesting that both agents might be used together for an increased antifibrotic effect. RLX caused increased expression of the PPARγ target genes CD36 and LXRα. RLX's effect was mimicked by forskolin and partially blocked by pertussis toxin, suggesting that RLX works through a cAMP/protein kinase A pathway to activate PPARγ. A better understanding of this pathway might help in the amelioration of fibrotic diseases.