Supplementing diets with high potassium helps reduce hypertension in humans. Inwardly rectifying K+ channels K ir 4.1 (Kcnj10) and K ir 5.1 (Kcnj16) are highly expressed in the basolateral membrane of distal renal tubules and contribute to Na+ reabsorption and K+ secretion through the direct control of transepithelial voltage. To define the importance of K ir 5.1 in blood pressure control under conditions of salt-induced hypertension, we generated a Kcnj16 knockout in Dahl salt-sensitive (SS) rats (SS Kcnj16–/–). SS Kcnj16–/–rats exhibited hypokalemia and reduced blood pressure, and when fed a high-salt diet (4% NaCl), experienced 100% mortality within a few days triggered by salt wasting and severe hypokalemia. Electrophysiological recordings of basolateral K+ channels in the collecting ducts isolated from SS Kcnj16–/–rats revealed activity of only homomeric K ir 4.1 channels. K ir 4.1 expression was upregulated in SS Kcnj16–/–rats, but the protein was predominantly localized in the cytosol in SS Kcnj16–/–rats. Benzamil, but not hydrochlorothiazide or furosemide, rescued this phenotype from mortality on a high-salt diet. Supplementation of high-salt diet with increased potassium (2% KCl) prevented mortality in SS Kcnj16–/–rats and prevented or mitigated hypertension in SS Kcnj16–/–or control SS rats, respectively. Our results demonstrate that K ir 5.1 channels are key regulators of renal salt handling in SS hypertension.