Anion gap acidosis is generally regarded as featuring a rather precise balance between the decrement in plasma HCO-3 and the increment in anion gap plasma Cl- remaining normal. In theory, therefore, the finding of hypochloremia in conjunction with an anion gap acidosis should evidence a coexisting metabolic alkalosis. In the clinical setting, however, hypochloremia is occasionally found in patients with anion gap acidosis but without exposure to a recognized alkalosis-inducing process. To examine the possibility that an element of hypochloremia might, under certain circumstances, be an integral part of the underlying acidosis, we studied three forms of anion gap acidosis in unanesthetized, nephrectomized rats. In protocol I, 7 mEq/kg H+ as H2SO4 was infused over 1 hour. In protocol II, 24 mEq/kg H+ as D,L-lactic acid was infused over 3 hours. In protocol III, rats were maintained in the anephric state for approximately 28 hours to permit uremic acidosis to develop. In each protocol, plasma C1- fell significantly (-8.0, -12.0, and -7.0 mEq/L in protocols I, II, and III, respectively) and contributed substantially to the observed increment in anion gap. A possible explanation for this acidosis-induced hypochloremia is expansion of the extracellular compartment secondary to the extrusion of cellular cation that occurs in the process of buffering.