Sodium depletion has a protective effect on target-organ damage in hypertension independent of blood pressure. Here we tested whether chronic dietary sodium restriction may prevent the development of renal alterations associated with insulin resistance by reducing the inflammatory and oxidant state. Rats were fed normal-salt-60% fructose, low-salt-60% fructose, or control normal-salt diet for 12 weeks. Insulin resistance induced by high-fructose diet was associated with an increase in albuminuria, tubular and glomerular hypertrophy, and inflammation of kidney and adipose tissue. The low-salt diet improved insulin sensitivity and prevented kidney damage. These beneficial effects of sodium depletion were associated with a decrease in renal inflammation (macrophage infiltration, IL-6, TNF-α) and oxidative stress (NADPH oxidase activity), and a prevention of histologic changes in retroperitoneal fat induced by high fructose. Thus, dietary salt depletion has beneficial effects on renal and metabolic alterations associated with a high-fructose diet in rats.