OBJECTIVES: Fatigue is an important symptom for multiple sclerosis (MS) patients. Qualitative research supported initial content validity of the FSIQ-RMS™, the first patient-reported outcome (PRO) measure of fatigue in relapsing (R)MS developed according to the 2009 FDA PRO guidance. To confirm appropriateness, validity, and reliability of the FSIQ-RMS, further psychometric analyses were required. METHODS: The FSIQ-RMS™ with 9 Symptom items (daily recall period, 1 subdomain) and 14 Impact items (weekly recall period, 3 subdomains) was administered over 3 months (three 7-day intervals) in a multicenter, non-interventional, US-based, IRB-approved study to adult patients with different RMS subtypes (relapsing remitting, secondary progressive, progressive relapsing) and a subset of matched healthy controls (week 1 only). Data analyses included: item response and dimensionality; content and construct validity; internal consistency and test-retest reliability; as well as attribution of fatigue to RMS. Evaluations were supported by those from a cross-sectional, multicenter study, in which RMS patients completed the FSIQ-RMS™ Symptoms domain. RESULTS: The psychometric validation study included 164 RMS patients (mean age 45 [range 19–65] years; 76% female) and 74 controls (40 [18–65] years; 73% female). Two redundant Symptom items were deleted, leaving 7; Impact items were unchanged. A 0–100 scoring algorithm was developed for the FSIQ-RMS™ (sub)domains. Internal consistency (Cronbach’s alpha 0.87–0.97) and test-retest reliability (intraclass correlation coefficient [ICC] 0.92–0.95) of all (sub)domains exceeded pre-specified thresholds (alpha>0.70; ICC≥0.70). The Symptoms domain discriminated along the symptom-severity continuum of RMS patients and between patients and healthy controls. Patients were able to attribute fatigue-related symptoms to RMS (14-point difference vs. controls; P<0.0001). Findings were supported by those from the cross-sectional study (N=154). CONCLUSIONS: Content and measurement validity of the revised final FSIQ-RMS™ were confirmed. Responsiveness of the PRO will be evaluated in a Phase III trial. Value Health