Chronic consumption of a high-fat, refined carbohydrate (HFS) diet causes hypertension. In an earlier study, we found increased nitric oxide (NO) inactivation by reactive oxygen species (ROS) and functional NO deficiency in this model. Given the critical role of NO in renal sodium handling, we hypothesized that diet-induced hypertension may be associated with salt sensitivity. Female Fischer rats were fed either a HFS or a standard low-fat, complex-carbohydrate (LFCC) rat chow diet starting at 2 months of age for 2 years. Arterial blood pressure, renal neuronal NO synthase (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS) protein, nitrotyrosine abundance (a marker of NO inactivation by ROS) and urinary NO metabolite excretion (NOx) were measured. To assess salt sensitivity, the blood pressure response to a high-salt (4%) diet for 1 week was determined. After 2 years, renal nNOS and urinary NOx were significantly depressed, while arterial pressure, eNOS, iNOS and nitrotyrosine were elevated in the HFS group but remained virtually unchanged in the LFCC group. Consumption of the high-salt diet resulted in a significant rise in arterial pressure in the HFS group but not the LFCC. Thus, chronic consumption of a HFS diet results in hypertension and salt sensitivity which may be in part due to a combination of reactive oxygen species-mediated NO inactivation and depressed renal nNOS protein expression.