We previously reported that laminar flow activates peroxisome proliferator-activated receptor γ (PPARγ) in vascular endothelial cells in a ligand-dependent manner that involves phospholipase A2 and cytochrome P450 epoxygenases. In this study, we investigated whether epoxyeicosatrienoic acids (EETs), the catalytic products of cytochrome P450 epoxygenases, are PPARγ ligands. Competition and direct binding assays revealed that EETs bind to the ligand-binding domain of PPARγ with K_d in the μM range. In the presence of adamantyl-ureido-dodecanoic acid (AUDA), a soluble epoxide hydrolase (sEH)-specific inhibitor, EETs increased PPARγ transcription activity in endothelial cells and 3T3-L1 preadipocytes. Inclusion of AUDA in the perfusing media enhanced, but overexpression of sEH reduced, the laminar flow-induced PPARγ activity. Furthermore, laminar flow augmented cellular levels of EETs but decreased sEH at the levels of mRNA, protein, and activity. Blocking PPARγ by GW9662 abolished the EET/AUDA-mediated antiinflammatory effect, which indicates that PPARγ is an effector of EETs.