Antidepressant treatment trials of irritable bowel syndrome (IBS) have suggested beneficial effects. Twenty-eight patients with the disorder (9 constipation-predominant, 19 diarrhea-predominant) completed a double-blind crossover study using desipramine, atropine, and placebo in random sequence. A four-week observation period preceded three six-week test periods. Bowel habits, abdominal distress, and affect were reported daily and in biweekly evaluations. Psychological assessments and rectosigmoid contractile studies were done in each period. Stool frequency, diarrhea, abdominal pain, depression, and slow contractions decreased significantly more in diarrhea-predominant patients during desipramine compared with placebo and atropine treatments. Diarrhea-prone patients' depression scores fell more in all periods than constipation-prone patients. Fifteen patients (13 diarrhea-predominant) improved globally during desipramine, five during placebo and six during atropine treatments. Desipramine may be helpful in treating IBS, perhaps through antidepressant and antimuscarinic effects.