Abstract Fatigue is a common and clinically challenging symptom in patients with inflammatory bowel diseases (IBD), occurring in ~ 50% of patients with quiescent disease. In this study, we aimed to investigate whether fatigue in patients with clinically quiescent IBD is reflected by circulating inflammatory proteins, which might reflect ongoing subclinical inflammation. Ninety-two (92) different inflammation-related proteins were measured in plasma of 350 patients with clinically quiescent IBD. Quiescent IBD was defined as clinical (Harvey-Bradshaw Index < 5 or Simple Clinical Colitis Activity Index < 2.5) and biochemical remission (C-reactive protein < 5 mg/L and absence of anemia) at time of fatigue assessment. Leukemia inhibitory factor receptor (LIF-R) concentrations were inversely associated with severe fatigue, also after adjustment for confounding factors (nominal P  < 0.05). Although solely LIF-R showed weak ability to discriminate between mild and severe fatigue (area under the curve AUC = 0.61, 95%CI: 0.53–0.69, P  < 0.05), a combined set of the top seven (7) fatigue-associated proteins (all P  < 0.10) was observed to have reasonable discriminative performance (AUC = 0.82 95%CI: 0.74–0.91, P  < 0.01). Fatigue in patients with IBD is not clearly reflected by distinct protein signatures, suggesting there is no subclinical inflammation defined by the studied inflammatory proteins. Future studies are warranted to investigate other proteomic markers that may reflect fatigue in clinically quiescent IBD.