The Mediterranean diet is characterized by consumption of unsaturated fats with vegetables rich in nitrite and nitrate, resulting in endogenous formation of nitro fatty acids. These reactive lipids adduct to soluble epoxide hydrolase, inhibiting it to lower blood pressure. Mice genetically engineered to be resistant to this adductive inhibition had high blood pressure basally and their hydrolase activity was fully resistant to inhibition by nitro fatty acid supplied directly or generated via the Mediterranean diet. Similarly nitro fatty acid lowered blood pressure and abrogated cardiac hypertrophy in a hypertension model in wild-type mice, but was ineffective in mutant mice. Thus, protection from hypertension afforded by the Mediterranean diet is mediated by nitro-fatty acid-dependent inhibition of soluble epoxide hydrolase.