ClC chloride channels are found in all three kingdoms of life though little is known about their functions in prokaryotes. Here we investigated the role of a Vibrio cholerae ClC channel in acid resistance and intestinal colonization. The putative V. cholerae ClC channel was found to confer mild resistance to acid when pH was adjusted with HCl, but not with other acids. Surprisingly, a ClC channel deletion mutant exhibited enhanced intestinal colonization in infant mice.