To examine the effect of carbonic anhydrase inhibition on proximal tubular electrolyte reabsorption, plasma pH was altered before and after acetazolamide administration in six volume-expanded dogs during continuous infusion of ethacrynic acid to inhibit transcellular NaCl reabsorption. Plasma pH was altered by changing PCO2, keeping plasma bicarbonate concentration and glomerular filtration rate constant. Linear inverse relationships were obtained between electrolyte reabsorption and plasma pH. Before acetazolamide administration, a change in plasma pH of 0.1 unit from pH 7.4 altered bicarbonate reabsorption by about 10% and sodium and chloride reabsorption remaining during ethacrynic acid infusion by about 6.5%. Administration of acetazolamide (30 mg/kg b.wt.) caused a reduction in electrolyte reabsorption at all plasma pH levels examined. A further reduction occurred after increasing the dose to 100 mg/kg b.wt. The absolute inhibitory effects were almost twice as large during hypercapnia as during hypocapnia whereas the reduction in fractional reabsorption was the same at all plasma pH levels. Both variations in plasma pH and administration of acetazolamide altered the reabsorption of bicarbonate, chloride and sodium in molar ratios of about 1:2:3. Hence, acetazolamide inhibits a constant fraction of the NaHCO3 reabsorption and the associated NaCl reabsorption in the proximal tubules independent of changes in plasma pH.