The effects of extracellular pH and beta-adrenergic stimula-tion on the volume and pH of rainbow. trout red cells were studied in HCO₃^-/ CO₂ butfered media. A decrease in extracellular pH caused an increase in red cell volume and a decrease in intracellular pH. The pH-induced changes in cell volume were inhibited by 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic acid, (DIDS), an inhibitor of the anion exchange pathway, but not by amiloride, an inhibitor of Na⁺/H⁺ exchange, indicating that these volume changes are mainly associated with movements of chloride across the red cell membrane, and that the Na⁺/H⁺ exchanger is not activated by changes in intracellular pH alone. The adrenergic drug, isoproterenol, promoted cell swelling and proton extrusion even in the presence of 10 mM HCO₃^-, showing that the adrenergic response plays a significant role in the control of cytoplasmic pH. These responses were enhanced by a decrease in extracellular pH, showing that the adrenergic response is of benefit to stressed animals. DIDS markedly enhanced the effect of isoproterenol on the pH_i, but abolished the increase in red cell volume. The effects of furosemide were similar to those of DIDS, suggesting that these transport inhibitors have a similar mode of action. Amiloride, on the other hand, inhibited both the volume and the pH changes associated with adrenergic stimulation. These observations support the double Na⁺/H⁺ and HCO₃^-/CI^- exchange model of adrenergic swelling in fish red cells.