SUMMARY Dahl “S” rats become hypertensive wben fed > high salt (NaCl) diet but remain normotensive on a low NaCl diet. Dahl “R” rats are normotensive on either diet. For a given perfusion pressure, isolated “S” kidneys excrete 50% less sodium than “R” kidneys. Therefore, we searched for a sodium-retaining hormone in “S” rats. Kidneys were isolated without ischemia from normal rats and were continuously perfused at 125 mm Hg with blood from Dahl “S” and “R” rats, all on low NaCl diets. All kidney and adrenal tissue had been extirpated from the perfusing rats. During 15 minutes of perfusion, the isolated “normal” kidneys excreted a mean of 164 jtEq Na/rain/100 g during 26 perfusion experiments with blood from “R” rats. The “normal” kidneys excreted a mean of 84 j*Eq Na during 24 perfusions with blood from “S” rats. Thus, the normal kidneys excreted half as much sodium wben perfused with “S” blood compared with “R” blood (p < 0.02). Seemingly, a Na-retainlng humoral agent is present in the blood of “S” rats on a low Na diet, in the absence of renal and adrenal tissue. Moreover, in these normal kidneys, perfusion with “S” blood induced a 16% higher renal vascular resistance than perfusion with “R” blood (p < 0.01), indicating vasoconstricting agents in “S” blood. However, the Na-retaining humoral effect is definitely not dependent on the vasoconstriction. The Na-retaining humoral effect in “S” blood could lead to Na retention by “S” kidneys in vivo, which could partially account for the susceptibility of “S” rats to NaCl hypertension. Furthermore, both “S” and “R” perfusing rats were continuously expanded with two-thirds blood and one-third Ringer's solution at a rate of 5% of body weight per hour. This expansion induced the appearance of a natriuretic humoral agent in the blood of both “S” and “R” rats to an equal degree, so that after 45 minutes of expansion, the isolated kidneys had increased their Na excretion approximately twofold. Hypertension is readily induced in Dahl “S” rats by feeding them a high NaCl diet. However, this hypertension can be almost completely prevented by concomitant treatment with thiazide diuretics that act mainly on the kidney to facilitate sodium excretion. This result is in agreement with the hypothesis that a shift in the pressure nttriuresis curve, reducing Na excretion for a given arterial pressure, is partially responsible for the great sensitivity to NaCl hypertension in the “S” rat. The Naretaining hormone may contribute to this shift.