Aberrant epithelial fluid and HCO3− secretion is associated with many diseases. The activity of HCO3− transporters depends of HCO3− availability that is determined by carbonic anhydrases (CAs). Which CAs is essential for epithelial function is unknown. CA12 stands out since the CA12(E143K) mutation causes salt wasting in sweat and dehydration in humans. Here, we report that expression of CA12 and of CA12(E143K) in mice salivary glands increased and prominently inhibited, ductal fluid secretion and salivation in vivo. CA12 markedly increases the activity and is the major HCO3− supplier of ductal Cl−/HCO3− exchanger AE2, but not of NBCe1‐B. The E143K mutation alters CA12 glycosylation at N28 and N80, resulting in retention of the basolateral CA12 in the ER. Knockdown of AE2 and of CA12 inhibited pancreatic and salivary glands ductal AE2 activity and fluid secretion. Accordingly, patients homozygous for the CA12(E143K) mutation have dry mouth, dry tongue phenotype. These findings reveals an unsuspected prominent role of CA12 in epithelial function, explains the disease and calls for caution in the use of CA12 inhibitors in cancer treatment. This article is protected by copyright. All rights reserved