We studied 27 patients with severe chronic diarrhea for which extensive investigations carried out at other institutions had failed to reveal a diagnosis. They were studied by standard diagnostic methods as well as by careful fecal analysis and intestinal perfusion. If they were incontinent of feces, anal sphincter function tests were performed. Although many were suspected of having pancreatic cholera syndrome, this diagnosis could not be established in a single patient. The most common diagnosis that could be established was surreptitious ingestion of drugs (laxatives in 7 patients and diuretics in 2). Other specific diagnoses included ulcerative colitis in 2 patients, allergy to beef in 1, and bacterial overgrowth of the small intestine in 1. Thus, we were able to establish a specific diagnosis in 13 patients. Of the remaining 14 patients, 8 had findings suggestive of irritable bowel syndrome, and 2 others had anal sphincter dysfunction as the major cause of their disability. The other 4 undiagnosed patients had severe secretory (3 patients) or osmotic (1 patient) diarrhea. Follow-up interviews at 6 mo-6 yr failed to reveal evidence of a cause for diarrhea that had been overlooked during our studies. The diagnostic approach to patients with unexplained diarrhea is discussed. The importance of a search for surreptitious drug ingestion and accurate measurement of bowel movement frequency and stool weight is emphasized.