Lactose malabsorption is characterized by a deficiency of mucosal lactase. As a consequence, lactose reaches the colon where it is broken down by bacteria to short-chain fatty acids, CO2, and H2. Bloating, cramps, osmotic diarrhea, and other symptoms of irritable bowel syndrome are the consequence and can be seen in about 50% of lactose malabsorbers. Having made the observation that females with lactose malabsorption not only showed signs of irritable bowel syndrome but also signs of premenstrual syndrome and mental depression, it was of interest to establish whether a statistical correlation existed between lactose malabsorption and mental depression. Thirty female volunteers were analyzed by measuring breath H2 concentrations after an oral dose of 50 g lactose and were classified as normals or lactose malabsorbers according to their breath H2 concentrations. All patients filled out a Beck's depression inventory questionnaire. Of the 30 female volunteers, six were lactose intolerant (20%) and 24 were normal lactose absorbers (80%). Subjects with lactose malabsorption showed a significantly higher score in the Beck's depression inventory than normal lactose absorbers did. The data thus suggest that lactose malabsorption may play a role in the development of mental depression. In lactose malabsorption high intestinal lactose concentrations may interfere with L-tryptophan metabolism and 5-hydroxytryptamine (serotonin) availability. Lactose malabsorption should be considered in patients with signs of mental depression.