An elevated plasma pH and bicarbonate are the clinical hallmarks of metabolic alkalosis. Nevertheless, to fully define its pathophysiology, one needs a quantitative interpretation of events in 3 areas - the ECF, ICF, and urine. Accordingly, our purpose was to study mass balance in Cl--depletion metabolic alkalosis with normal initial balance for Na+ and K+. In the 20 h following the "exchange" of Cl- (loss, 2455 mumol) and HCO(3-) (gain, 2455 mumol), only 334 mumol HCO(3-) remained in the ECF and 337 mumol were excreted. The remaining 1784 mumol disappeared primarily via titration because 3051 mueq of endogenous anions were produced and excreted largely with K+. Accordingly, metabolic alkalosis was associated with a deficit rather than a surplus of HCO(3-). To reflect the shift of H+ into cells driven by the exit of K+, the cumulative deficit of Cl- was replaced as KCl or NaCl. The fall in plasma [HCO(3-)] was larger in the KCl group (13.2 vs. 9.4 mmol/L); it was largely due to H+ exit from cells; in contrast, disappearance of HCO(3-) from the ECF was due to new endogenous acid production in the NaCl group. Thus, there was an overall deficit of HCO(3-) in metabolic alkalosis associated with KCl depletion (extracellular alkalosis and intracellular acidosis); processes in the ICF were not corrected by NaCl.