Non-nutrient dependent salt absorption across the brush border membrane of intestinal epithelial cells is primarily mediated by coupled apical Na⁺-H⁺ (aNHE) and anion exchange transport, the latter suspected of being mediated by DRA (Down-Regulated in Adenoma, SLC26A3) that is defective in congenital chloridorrhea. To investigate DRA in greater detail and determine if DRA and NHE activities can be coupled, ²²Na⁺ and ³⁶Cl^- uptake were measured in Caco2BBE colon cells infected with the tet-off-inducible DRA transgene. Under basal conditions, DRA activity was low in normal and infected Caco2BBE cells in the presence of tetracycline, whereas NHE activities could be easily detected. When apical NHE activity was increased by transfection or serum-induced expression of the aNHE isoforms, NHE2 and NHE3, increased ³⁶Cl uptake is observed. DRA activity was inhibited by niflumic acid greater than DIDS as well as by the sodium/hydrogen exchange inhibitor dimethylamiloride and the carbonic anhydrase inhibitor methazolamide. DRA activity was largely aNHE-dependent, whereas a component of DRA-independent aNHE uptake continued to be observed. Coupled aNHE and DRA activities were inhibited by increased cellular cAMP and calcium and were associated with synaptotagmin I-dependent, clathrin-mediated endocytosis. In summary, these data support the role of DRA in electroneutral NaCl absorption involving functional coupling of Cl^-/base exchange and apical NHE.