A 49-yr-old patient developed severe chronic secretory diarrhea associated with hypokalemia and gastric hypochlorhydria. Small bowel perfusion study revealed active proximal intestinal secretion. Despite thorough investigation, the cause of her secretory diarrhea was not elucidated. Her diarrhea was refractory to indomethacin, prednisone, and trifluoperazine therapy. The life-threatening profuse watery diarrhea responded, however, to oral lithium carbonate, an agent reported to inhibit cyclic adenosine monophosphate synthesis. Diarrhea stopped within 4 days of initiation of lithium chloride therapy. Discontinuation of lithium 2 wk later resulted in return of watery diarrhea. Lithium therapy was reinstituted and her diarrheal symptoms resolved completely. Three months later, lithium carbonate was discontinued. The patient continued to be well and remained asymptomatic 15 mo after discontinuation of therapy. Therefore, in patients with chronic secretory diarrhea in whom exhaustive tests fail to reveal an etiology, a trial of oral lithium therapy may be beneficial in ameliorating the disabling symptoms and could be life-saving.