Background & Aims: A high proportion of patients with irritable bowel syndrome (IBS) respond to placebo in clinical trials (estimated at about 40%). We aimed to identify factors that contribute to the high placebo response rate using data from a placebo-controlled trial of patients with IBS. Methods: We performed a retrospective analysis of 599 women with IBS with constipation who were in the placebo group of a 12-week, randomized, double-blind, phase 3 trial of the experimental medication renzapride. Primary analyses evaluated frequency of abdominal pain in patients who received placebo, defined as ≥30% pain improvement from baseline for ≥6 of the 12 study weeks. We performed backward elimination regression with bootstrapping to identify factors associated with response to placebo. Results: In the placebo group, 29.0% of the patients had an abdominal pain response. Factors associated with a response to placebo were baseline variation in abdominal pain (odds ratio [OR], 1.71), maximum baseline pain severity (OR, 1.34), and placebo response in study week 2 (OR, 2.23) or week 3 (OR, 3.69). Factors associated with lack of response to placebo were number of baseline complete spontaneous bowel movements (OR, 0.73; P = .019) and final baseline pain ratings (OR, 0.73; P < .001). Conclusions: We identified factors associated with a response in abdominal pain to placebo using original data from an IBS clinical trial. Baseline factors associated with the placebo response in women with IBS and constipation included variation in baseline pain symptoms, severity of baseline symptoms, and early improvement of abdominal pain. These findings have significant implications for clinical trial design.