OBJECTIVES: A 12-week prospective, observational study was conducted to evaluate the psychometric properties of the Brief Fatigue Inventory-Short Form (BFI-SF) and determine its appropriate use and performance for the measurement of fatigue in systemic lupus erythematosus (SLE) clinical trials. METHODS: Participants ≥18 years, who self-reported a physician diagnosis of SLE (confirmed by medical record review) and active SLE demonstrated by a Systemic Lupus Activity Questionnaire (SLAQ) score ≥11 (0-44 scale), were recruited using a free electronic medication monitoring service. All participants completed the BFI-SF, Multidimensional Assessment of Fatigue (MAF), and Short Form-36 (SF-36) electronically at baseline, week 2, and week 12. Score distributions, internal consistency, test-retest reliability, and construct validity were evaluated. RESULTS: A total of 122 participants were included in the study. The mean age was 45.7 years, 95.9% were female, and 68.9% were non-Hispanic white. Cronbach’s alpha were >0.9 for all BFI-SF items. Test-retest reliability of the BFI-SF showed a stable intraclass correlation for item #7 (ICC 0.76), and BFI domain scores had higher correlations (around 0.5) than most items (around 0.3-0.4). Construct validity was measured by strength of the correlations of the BFI-SF severity domains and global scores, and was moderately positively correlated to the SLAQ score (r>0.4). The domain and global scores were moderately negatively correlated to the SF-36 Vitality and Physical Function domains and SF-36 Physical Component score (r<-0.3). The BFI-SF item #3 for worst fatigue was highly positively correlated to the MAF (r=0.6). Patients with less severe fatigue (MAF≤36) scored lower than patients with more severe fatigue (MAF>36) on all domains of the BFI-SF (total score, 4.66±1.55 vs. 6.80±1.13; p<0.0001). CONCLUSIONS: Assessment of fatigue severity as measured by the BFI-SF demonstrated validity and reliability in a sample of patients with moderate-to-severe SLE and may be used as a patient-reported outcome tool in clinical trials.