Introduction: Performance of health care professionals depends on both medical knowledge and the certainty with which they possess it. Conventional continuing medical education interventions assess the correctness of learners' responses but do not determine the degree of confidence with which they hold incorrect information. This study describes the use of confidence-based learning (CBL) in an activity designed to enhance learners' knowledge, confidence in their knowledge, and clinical competence with regard to constipation-predominant IBS (IBS-C), a frequently underdiagnosed and misdiagnosed condition. Methods: The online CBL activity included multiple-choice questions in 2 modules: Burden of Care (BOC; 28 questions) and Patient Scenarios (PS; 9 case-based questions). After formative assessment, targeted feedback was provided, and the learner focused on material with demonstrated knowledge and/or confidence gaps. The process was repeated until 85% of questions were answered correctly and confidently (ie, mastery was attained). Results: Of 275 participants (24% internal medicine, 13% gastroenterology, 32% family medicine, and 31% other), 249 and 167 completed the BOC and PS modules, respectively. Among all participants, 61.8% and 98.2% achieved mastery in the BOC and PS modules, respectively. Baseline mastery levels between specialties were significantly different in the BOC module (p = 0.002); no significant differences were evident between specialties in final mastery levels. Approximately one-third of learners were confident and wrong in topics of epidemiology, defining IBS and constipation, and treatments in the first iteration. No significant difference was observed between specialties for the PS module in either the first or last iterations. Discussion: Learners achieved mastery in topics pertaining to IBS-C regardless of baseline knowledge or specialty. These data indicate that CME activities employing CBL can be used to address knowledge and confidence gaps. (Contains 7 figures and 3 tables.)