The evolution of accessory air-breathing structures is typically associated with reduction of the gills, although branchial ion transport remains pivotal for acid–base and ion regulation. Therefore, air- breathing fishes are believed to have a low capacity for extracellular pH regulation during a respiratory acidosis. In the present study, we investigated acid–base regulation during hypercapnia in the air- breathing fish Pangasianodon hypophthalmus in normoxic and hypoxic water at 28–30°C. Contrary to previous studies, we show that this air-breathing fish has a pronounced ability to regulate extracellular pH ( pHe) during hypercapnia, with complete metabolic compensation of pHe within 72 h of exposure to hypoxic hypercapnia with CO2 levels above 34 mmHg. The high capacity for pHe regulation relies on a pronounced ability to increase levels of HCO3− in the plasma. Our study illustrates the diversity in the physiology of air-breathing fishes, such that generalizations across phylogenies may be difficult.