Blood pH recovery was associated with elevated plasma [HCO3−] (Figs. 3,4) and an equimolar reduction in plasma [Cl−] (Fig. 4). Net plasma HCO3−/Cl− exchange during exposure to hypercarbia is the typical pattern observed in teleosts20, and these data imply it likely represents the basal condition. Other plasma ions were unchanged ([Na+], [Mg2+], and [Ca2+]; Fig. 3). The calculated net acid excretion rate for hagfish was similar to that of other fish species investigated (Supplementary Table 1), but what stands out in the physiological response to hypercarbia is the degree of pHe compensation, as well as the associated quantitative changes in plasma [HCO3−] and [Cl−]. No other water-breathing craniate has been reported to either tolerate ~1.2 pH blood acidosis or to recover pHe to this degree. This impressive pHe compensation during acute hypercarbia was driven entirely by an unprecedented increase in plasma [HCO3−], in exchange for [Cl−], which reached 78.2 (±4.5) and 75.4 (±8.2) mM during exposure to 30 and 50 mm Hg pCO2 (Figs. 3,4), respectively. These values are over twice the next highest plasma [HCO3−] ever reported for a water-breathing vertebrate during acute exposure to hypercarbia20. Typically, water-breathing fish exposed to acute (≤96 h) hypercarbia are unable to elevate blood HCO3− beyond 25–33 mM, termed the “bicarbonate concentration threshold”20 (Fig. 3). In any case, the gills of hagfish appear to be an efficacious structure for acid-base regulation with a compensatory capacity that far exceeds that of any other aquatic craniate investigated to date.