Significance This study provides molecular evidence indicating that female hormone/estrogen enables inhibition of vascular soluble epoxide hydrolase (sEH) expression in physiological conditions via an epigenetic-based regulatory mechanism, leading to an increase in the vascular level of epoxyeicosatrienoic acids (EETs) that: ( i ) possess cardio-protective properties, such as vasodilation, resulting in better blood supply to tissues and lower blood pressure, and ( ii ) are degraded/inactivated by sEH. To this end, increases in tissue EETs, as a consequence of estrogen suppression of sEH to reduce EET degradation, can serve as an explanation, at least in part, of why women in general perform better cardiovascular functions, associated with lower incidence of ischemic cardiovascular diseases, compared with men.