In salt-resistant phenotypes, chronic elevated dietary sodium intake evokes suppression of renal sodium-retaining mechanisms to maintain sodium homeostasis and normotension. We have recently shown that brain Gαi 2 protein pathways are required to suppress renal sympathetic nerve activity and facilitate maximal sodium excretion during acute intravenous volume expansion in Sprague-Dawley rats. Here, we studied the role of brain Gαi 2 proteins in the endogenous central neural mechanisms acting to maintain fluid and electrolyte homeostasis and normotension during a chronic elevation in dietary salt intake. Naive or bilaterally renal denervated adult male Sprague-Dawley rats were randomly assigned to receive an intracerebroventricular scrambled or Gαi 2 oligodeoxynucleotide infusion and then subjected to either a normal salt (0.4%) or high-salt (8.0%) diet for 21 days. In scrambled oligodeoxynucleotide-infused rats, salt loading, which did not alter blood pressure, evoked a site-specific increase in hypothalamic paraventricular nucleus Gαi 2 protein levels and suppression of circulating norepinephrine content and plasma renin activity. In salt-loaded rats continuously infused intracerebroventricularly with a Gαi 2 oligodeoxynucleotide, animals exhibited sodium and water retention, elevated plasma norepinephrine levels, and hypertension, despite suppression of plasma renin activity. Furthermore, in salt-loaded bilaterally renal denervated rats, Gαi 2 oligodeoxynucleotide infusion failed to evoke salt-sensitive hypertension. Therefore, in salt-resistant rats subjected to a chronic high-salt diet, brain Gαi 2 proteins are required to inhibit central sympathetic outflow to the kidneys and maintain sodium balance and normotension. In conclusion, these data demonstrate a central role of endogenous brain, likely paraventricular nucleus-specific, Gαi 2 -subunit protein–gated signal transduction pathways in maintaining a salt-resistant phenotype.