1. The effect of varying the Pco2 on the buffering of mineral acid has been investigated. HCl (6 mmol/kg) was infused into anaesthetized-paralysed dogs maintained on a respirator and changes in Pco2 (between 20 and 60 mmHg) were arranged by varying the stroke volume. 2. No significant interaction between buffering of respiratory and metabolic events was discerned. Variations in Pco2 did not alter the efficiency of the buffering of the HCl. The presence or absence of metabolic acidosis did not alter the magnitude of the effect of acute respiratory change on the concentration of extracellular bicarbonate. This response remained between 1·0 and 1·3 mmol/l for changes of 10 mmHg in the Pco2. 3. The buffering of HCl achieved outside the blood and extracellular fluids did not correlate with measured changes in extracellular pH or with predicted changes in intracellular pH. This buffering appears to be associated with changes in the H+ ion concentration gradient across the cell membranes.