The activity and the isozyme B and C levels of red cell carbonic anhydrase was examined before and during CO2 inhalation in 18 patients with chronic respiratory failure. Carbonic anhydrase B and C levels did not change during 5 min breathing of high (8-9%) and low (3-5%) CO2 mixture. Carbonic anhydrase activity decreased in patients with combined hypercarbia (Paco2 greater than or equal to 45 mmHg) and hypoxemia (Pao2 less than or equal to 60 mmHg). This was accompanied by an increase in red cell K+ content, 2, 3-DPG and Hct/Hb. The activity did not change in patients with only hypoxemia. Carbonic anhydrase activity and plasma HCO-3 concentration were positively correlated (r = 0.4, P less than 0.05). A significant inverse correlation was also found between changes in red cell K+ content and those in carbonic anhydrase activity (r = - 0.42, P less than 0.05). These results indicate that 1), there is a dissociation between activity and isozyme levels in red cell carbonic anhydrase during the initial 5 min of CO2 breathing in patients with combined hypercarbia and hypoxemia, and 2), there seems a linkage exists between K+ movement across the red cell membrane and carbonic anhydrase activity.