Berberine, an alkaloid from the plant Berberis aristata, which has been known since ancient times as an antidiarrheal medication in India and China, inhibited by approximately 70% the secretory responses of the heat-labile enterotoxins of Vibrio cholerae and Escherichia coli in the rabbit ligated intestinal loop model. The drug was effective when given either before or after enterotoxin binding and when given either intraluminally or parenterally; it did not inhibit the stimulation of adenylate cyclase by cholera enterotoxin and caused no histological damage to intestinal mucosa. Berberine also markedly inhibited the secretory response of E. coli heat-stable enterotoxin in the infant mouse model. Although the mechanism of action of the drug is not yet known, these data provide a rationale for its apparent clinical usefulness in treating acute diarrheal disease.