Metabolic syndrome is a combination of symptoms including obesity, dyslipidaemia, glucose intolerance and hypertension. Oxidative stress appears to be a pathophysiological factor that links these signs and encourages progression towards heart failure and diabetes. Nox4 is a hydrogen peroxide nicotinamide adenine dinucleotide phosphate(NADPH) oxidase isoform -found in various cardiovascular cells and tissues, but also in tissues such as the liver- which is involved in glucose and lipid homeostasis. To test whether inhibition of the Nox4 enzyme could improve blood pressure and metabolic parameters in mice receiving either angiotensinII or a high-fat diet. Systolic and diastolic arterial pressures, pulse rate and heart rate were obtained in 24male mice (12wild-type [WT] and 12Nox4-/-) before and during 14days of angiotensinII infusion. After angiotensinII infusion, cardiac histological remodeling was assessed. Weight and biochemical parameters were measured in 18male and 18female mice (nine WT and nine Nox4-/- per gender) after 10weeks on a standard chow diet, then 15weeks on a high-fat diet. Glucose tolerance and insulin sensitivity were tested at age 25weeks. Knock-out animals did not demonstrate a baseline blood pressure phenotype, but blocking Nox4 protected against angiotensinII-mediated arterial and pulse pressure increases. No protection against angiotensinII-induced cardiac fibrosis was observed. From a metabolic point of view, Nox4 inhibition reduced plasma triglycerides in male and female mice under a chow diet. However, Nox4 deletion did not affect the metabolic profile under a high-fat diet in males or females, but increased glucose intolerance in females. Our data identify Nox4 as a key source of radical oxygen species involved in hypertension and some metabolic problems.