Background: Although it is well recognized that fatigue is an important problem in many of the quiescent inflammatory bowel disease (IBD) patients, it is unknown whether the immune status is different in fatigued versus non-fatigued patients. In this study, we contrasted various characteristics of the immune system in fatigued against non-fatigued patients with IBD in clinical remission. Patients and methods: Patients with IBD in clinical remission were phenotyped according to the Montreal classification, and the checklist individual strength-fatigue (CIS-fatigue) was used to assess fatigue (CIS-fatigue ≥ 35). Flow cytometry on peripheral blood samples was used to investigate differences in leukocyte subsets. The expression of various cytokines was determined in stimulated whole blood and serum samples using enzyme-linked immunosorbent assay. Differences between fatigued and non-fatigued patients with IBD were assessed. Results: In total, 55 patients were included in the fatigue group (FG) and 29 patients in the non-fatigue group (NFG). No differences in demographic and clinical characteristics were observed between the groups. Flow cytometry data showed a significantly lower percentage of monocytes (p = 0.011) and a higher percentage of memory T-cells (p = 0.005) and neutrophils (p = 0.033) in the FG compared with the NFG. Whole blood stimulation showed increased TNF-α (p = 0.022) and IFN-γ (p = 0.047) in the FG. The median serum level was significantly higher for IL-12 (p < 0.001) and IL-10 (p = 0.005) and lower for IL-6 (p = 0.002) in the FG compared with NFG. Conclusion: Significant differences in immune profile between fatigued and non-fatigued patients with IBD in clinical remission wer