Changes in extracellular pH (pHo) in human red cell suspensions were monitored in a stopped-flow rapid reaction apparatus. A 20% suspension of washed human RBC in saline at pH 7 containing NaHCO3 and extracellular carbonic anhydrase was mixed with an equal volume of buffered saline solution at pH 6.7. Sodium salicylate, when present, was added to both the erythrocyte suspension and the buffer solution. The effects of salicylate in the therapeutic to toxic concentration range on HCO-3/Cl- exchange were studied at 37 degree C. HCO-3/Cl- exchange flux was estimated using the extracellular buffer capacity and the difference between dpHo/dt using a control RBC suspension and that using a suspension of RBC whose anion exchange pathway was markedly inhibited. The results show that salicylate competitively decreases the rate of HCO-3/Cl- exchange, with inhibition increasing as salicylate concentration increases. KI is approximately 2.4 mM. At a salicylate concentration of 10 mM, HCO-3/Cl- exchange under the conditions of our experiments was inhibited by more than 70%. These findings are consistent with the possibility that CO2 transfer in capillary beds in vivo may be diminished in the presence of salicylate due to slowing of red cell HCO-3/Cl- exchange.