Background: Fatigue is one of the most common and troubling symptoms of multiple sclerosis (MS) and more severe and disabling than fatigue in other somatic populations. Although fatigue seems MS specific, its pathogenesis is still poorly understood. Objective: To study the disease specificity of fatigue in MS by comparing its level, its physical and psychological correlates to those of patients with ulcerative colitis (UC), a peripheral chronic auto-immune disease. We focused on the relative contribution of disease severity, depression and negative affectivity to fatigue in both patient samples. Methods: A total of 88 MS and 76 UC patients were included in this cross-sectional study. Fatigue, depression and negative affectivity were assessed respectively with the physical and mental fatigue subscales of the Multidimensional Fatigue Inventory, the depression subscale of the Hospital Anxiety and Depression Scale, and the neuroticism subscale of the Dutch NEO Five-Factor Inventory. The Expanded Disability Status Scale and the Colitis Activity Index were used to measure disease severity in MS and UC patients respectively. Results: While levels of both physical and mental fatigue were significantly higher in MS patients than in UC patients, there were no group differences in the contribution of disease severity, depression and negative affectivity to both physical and mental fatigue. Conclusion: Although levels of fatigue are higher for MS patients when compared with UC patients, the correlates of fatigue do not indicate MS specificity. As such our results support a transdiagnostic approach to fatigue in MS.