Association of some plasma membrane bicarbonate transporters with carbonic anhydrase enzymes forms a bicarbonate transport metabolon to facilitate metabolic CO₂-HCO₃^- conversions and coupled HCO₃^- transport. The transmembrane carbonic anhydrase, CAIX, with its extracellular catalytic site, is highly expressed in parietal and other cells of gastric mucosa, suggesting a role in acid secretion. We examined in transfected HEK293 cells the functional and physical interactions between CAIX and the parietal cell Cl^-/HCO₃^- exchanger AE2 or the putative Cl^-/HCO₃^- exchanger, SLC26A7. Co-expression of CAIX increased AE2 transport activity by 28 ± 7% and also activated transport mediated by AE1 and AE3 (32 ± 10% and 37 ± 9%, respectively). In contrast, despite a transport rate comparable to that of AE3, co-expressed CAIX did not alter transport associated with SLC26A7. The CAIX-associated increase of AE2 activity did not result from altered AE2 expression or cell surface processing. CAIX was co-immunoprecipitated with the co-expressed SLC4 polypeptides AE1, AE2 and AE3, but not with SLC26A7. GST pull-down assays with a series of domain-deleted forms of CAIX revealed that the catalytic domain of CAIX mediated interaction with AE2. AE2 and CAIX co-localized in human gastric mucosa, as indicated by co-immunofluorescence. This is the first example of a functional and physical interaction between a bicarbonate transporter and a transmembrane carbonic anhydrase. We conclude that CAIX can bind to some Cl^-/HCO₃^- exchangers to form a bicarbonate transport metabolon.