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Objectives Fatigue is one of the most common and debilitating symptoms experienced by patients with systemic lupus erythematosus (SLE). Previous studies revealed the association of fatigue with various SLE and non-SLE-related factors. This study aims to explore the prevalence of fatigue and the factors that are associated with fatigue experienced by SLE patients in an outpatient rheumatology clinic setting. Design Prospective, observational study using a sample of convenience. Setting Outpatient rheumatology clinic at a tertiary care centre. Participants Consecutive subjects with SLE presenting for their outpatient visits enrolled in the ongoing Institutional Review Board-approved ‘Pathogenesis and Natural History of SLE’ protocol. Primary and secondary outcome measures Disease activity and organ damage accrual were measured by Safety of Estrogens in Lupus Erythematosus: National Assessment Version of the Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR DI), respectively. Fatigue was measured by the self-reported Fatigue Severity Scale (FSS), and a score of ≥4 was used to define clinically significant fatigue. Correlation analyses were done to determine the association between fatigue and patient demographics, and SLE disease activity and damage indices. Results were considered as statistically significant at p<0.05. All data analyses were carried out with the SAS program, release V.9.4 (SAS Institute). Results 183 patients completed the study, with a significant proportion (144/183) belonging to ethnic minorities. The overall FSS score was mean (±SD) 4±1.8 and SELENA-SLEDAI score of 3±2.6. The group reporting significant FSS scores ≥4 (N=95) included a higher proportion of White patients, more organ damage (SLICC/ACR DI score mean (±SD) 1.9±1.9) and higher body mass index (BMI) mean (±SD) 29.6±6.7 kg/m 2 ; as compared with the group with FSS scores <4(N=85), which had a higher proportion of Black patients (p=0.034), lower SLICC/ACR DI scores (1.1±1.3 (p=0.008)) and BMI 27.6±5.6 kg/m 2 (p=0.03). Conclusions Our study found that organ damage accrual, specifically pulmonary fibrosis and neuropathy as measured by SLICC-ACR DI and high BMI, is associated with clinically significant fatigue in SLE. Furthermore, our results support previous findings that fatigue is independent of SLE disease activity. Findings of our study need to be replicated in independent SLE cohorts measuring fatigue at multiple time points. Mechanistic studies are needed to better understand pathogenesis of fatigue in SLE.