Background: Crofelemer improves bowel function in several conditions characterized by states of prominent secretory diarrhea. AIM: This double-blind, randomized, placebo-controlled trial evaluated the effects of 3 dose levels of crofelemer in patients with diarrhea-predominant irritable bowel syndrome (D-IBS). Methods: Male and female patients were randomly assigned to receive crofelemer 125, 250 or 500 mg or placebo twice daily for 12 weeks. The primary efficacy measure was a responder for improvement in stool consistency. In addition, abdominal pain- and discomfort-free days, pain and discomfort scores as well as other bowel function parameters (such as stool frequency and consistency, urgency, bloating) were evaluated. Results: Two hundred and forty-two D-IBS patients were randomized. Crofelemer did not produce significant improvement in stool consistency (primary endpoint), stool frequency, urgency or adequate relief. However, female D-IBS patients showed improvement in the proportion of pain- and discomfort-free days during treatment with 500 mg crofelemer: month 1 (crofelemer vs. placebo: 17.7 vs. 10.2%, p = 0.098); month 2 (23.5 vs. 13.3%, p = 0.076); month 3 (26.1 vs. 10.6%, p = 0.0076). No benefit was seen in male D-IBS patients. Crofelemer was well tolerated. Conclusions: Crofelelmer did not produce benefit on bowel function; an increase in the number of pain- and discomfort-free days in female D-IBS patients was seen. Further studies with crofelemer are warranted to evaluate it as a potential visceral analgesic.