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ObjectivePatients with SLE frequently have debilitating fatigue and reduced physical activity. Intermuscular adipose tissue (IMAT) accumulation is associated with reduced physical exercise capacity. We hypothesised that IMAT is increased in patients with SLE and associated with increased fatigue, reduced physical activity and increased inflammation.MethodsIn a cross-sectional study, 23 patients with SLE and 28 control participants were evaluated. IMAT was measured in the calf muscles using sequentialT1-weighted MRI. Patient-reported physical activity and fatigue were measured and a multiplex proteomic assay was used to measure markers and mediators of inflammation.ResultsIMAT accumulation (percentage of IMAT area to muscle area) was significantly higher in SLE versus control participants (7.92%, 4.51%–13.39% vs 2.65%, 1.15%–4.61%, median, IQR, pConclusionPatients with SLE have greater IMAT accumulation than controls in the calf muscles. Increased IMAT is associated with greater fatigue and lower physical activity. Future studies should evaluate the effectiveness of interventions that improve muscle quality to alleviate fatigue in patients with SLE.