In salt-sensitive spontaneously hypertensive rats (SHR-S) of the Okamoto strain, dietary salt loading causes an exacerbation of hypertension that is associated with a decrease in noradrenergic input to the depressor neurons in the anterior hypothalamus. In the present study, the contribution of chloride to the salt-induced hypertensive response was examined in the SHR-S, in order to test the hypothesis that diets high in chloride but moderate in sodium elevate blood pressure in genetically predisposed subjects. SHR-S were fed diets high in NaCl (1.97% Na+, 2.93% Cl−; 5% NaCI), high in chloride (2.93%) but moderate in sodium (0.39%) or moderate in NaCl (0.39% Na+, 0.61% CI−; 1% NaCl). After 2 weeks, rats on the high (5%) NaCl diet exhibited a significant elevation in blood pressure compared to rats on the moderate (1 %) NaCl diet, and this elevation was maintained throughout the next 3 weeks. SHR-S on the high chloride diet were not significantly more hypertensive than 1% NaCl-fed SHR-S during the first 3 weeks, but during the fourth and fifth weeks, SHR-S on the high chloride diet displayed a significant exacerbation of hypertension. The diet-induced elevation in blood pressure in groups fed either the 5% NaCl or high chloride (compared to 1 % NaCl) diets was associated with significant decreases in norepinephrine stores in the anterior hypothalamic region, but no other changes in monoamines or monoamine metabolites in this region or in the posterior hypothalamic region. The high chloride diet did not increase blood pressure in normotensive Wistar-Kyoto rats. These data demonstrate that diets high in chloride and moderate in sodium can increase blood pressure in SHR-S and suggest that this increase is related to a reduction in noradrenergic input to sympathoinhibitory neurons in the anterior hypothalamus. © 1987 American Heart Association, Inc.