—To examine the role of the angiotensin II (AT)_1A receptor in the regulation of blood pressure and sodium balance, we measured systolic blood pressure responses in AT_1A receptor–deficient (Agtr1a−/−) and wild-type (Agtr1a+/+) mice while dietary sodium content was systematically altered. On a 0.4% sodium diet, systolic blood pressures were significantly lower in Agtr1a−/− than in +/+ mice. In Agtr1a+/+ mice, changing dietary sodium content did not affect blood pressure. In contrast, when Agtr1a−/− mice were fed a high-salt diet (6% NaCl), their systolic blood pressures increased significantly from 79±4 to 94±4 mm Hg (P<0.006). The low blood pressures of Agtr1a−/− mice decreased further while on a low-salt diet from 82±3 to 69±3 mm Hg (P<0.03). On the high-salt diet, urinary sodium excretion increased to similar levels in Agtr1a+/+ and −/− mice. Although urinary sodium excretion was substantially reduced in both groups during the low-salt diet, cumulative sodium balances became negative in Agtr1a−/− mice despite a 6-fold increase in urinary aldosterone. We infer, therefore, that the reduced blood pressures in Agtr1a−/− mice on a normal diet are caused by depletion of sodium and extracellular volume. Their “sodium sensitivity” suggests a critical role for renal AT_1A receptors to modulate sodium handling.