OBJECTIVES: Patient-reported outcome (PRO) instruments commonly used to measure fatigue in multiple sclerosis (MS) have not been developed according to the 2009 FDA PRO guidance. A qualitative research study was conducted to develop a new PRO, according to the guidance, measuring fatigue symptoms and impacts in relapsing MS (RMS). METHODS: Adult patients with relapsing-remitting MS (RRMS) were interviewed to elicit fatigue-related symptoms and impacts. Based on spontaneously reported symptoms, a draft PRO was developed. This was debriefed in cognitive interviews with further RRMS patients, and subsequently revised. Applicability of the PRO to other RMS populations was determined in content confirmation interviews with progressive-relapsing MS (PRMS) and relapsing secondary-progressive MS (RSPMS) patients. Institutional review board approval and participant informed consent were obtained before interviews. RESULTS: Participants were representative of RMS patients in clinical studies and practice; most had mild-to-moderate disease. Concept elicitation and cognitive debriefing included 17 (mean±SD age 43.9±13.3 [years]; 77% female) and 20 (47.0±12.0; 80% female) RRMS patients, respectively; content confirmation included 5 PRMS (52.6±12.5; 80% female) and 5 RSPMS (52.4±10.8; 60% female) patients. Saturation of concepts was reached during concept elicitation. Cognitive debriefing confirmed that participants understood PRO instructions, items, and response options as intended. The Fatigue Symptoms and Impacts Questionnaire-RMS (FSIQ-RMS™) comprises 23 items organized in a conceptual framework with 2 symptom domains (energy, muscle weakness) and 7 impact domains (daily activities, cognition, emotions, physical impact, self-care, sleep, social impact). As no novel concepts were reported by more than two patients per sub-group during content confirmation, the PRO was not revised. CONCLUSIONS: The FSIQ-RMS™ was demonstrated to be a comprehensive measure of fatigue-related symptoms and impacts in RMS patients, supporting initial content validity. Before it can be used in clinical practice or studies, final psychometric validation will be evaluated in a multicenter, observational trial in RMS patients.