Enteropathogenic E. coli is a food-borne pathogen that causes infantile diarrhea worldwide. EPEC decreases the activity and surface expression of the key intestinal Cl^-/HCO₃^- exchanger, SLC26A3 (DRA) contributing to the pathophysiology of early diarrhea. Little is known about the mechanisms governing membrane recycling of DRA. The current study investigated DRA trafficking under basal conditions and in response to EPEC utilizing Caco-2 cells. Apical Cl^-/HCO₃^- exchange activity was measured as DIDS-sensitive ¹²⁵I uptake. Cell surface biotinylation was performed to assess DRA endocytosis and exocytosis. Inhibition of clathrin-mediated endocytosis by chlorpromazine (60 μM) increased apical Cl^-/HCO₃^- exchange activity. Dynasore, a dynamin inhibitor also increased function and surface levels of DRA via decreased endocytosis. Perturbation of microtubules by nocodazole revealed that intact microtubules are essential for basal exocytic (but not endocytic) DRA recycling. Mice administered colchicine showed a decrease in DRA surface levels as visualized by confocal microscopy. In response to EPEC infection, DRA surface expression was reduced partly via an increase in DRA endocytosis and a decrease in exocytosis. These effects were dependent upon EPEC virulence genes espG1/G2. Intriguingly, EPEC induced decrease in DRA function was unaltered in the presence of dynasore, suggesting a clathrin-independent internalization of surface DRA. In conclusion, these studies establish the role of clathrin-mediated endocytosis and microtubules in the basal surface expression of DRA and demonstrate that EPEC-mediated decrease in DRA function and apical expression in Caco-2 cells involves decreased exocytosis.