Inflammatory bowel disease (IBD) is a chronic, relapsing noninfectious inflammatory condition of the intestinal tract with two main phenotypes, ulcerative colitis (UC) and Crohn's disease (CD), and globally increasing incidence and prevalence. Nearly 80% of the IBD patients with active disease and 50% of those with inactive disease suffer fatigue with significant impairment of their quality of life. Fatigue has been associated with multiple factors in IBD patients but, in most cases, no direct cause can be identified, and risk factors in clinically quiescent IBD are contradictory. Furthermore, as the assessment of fatigue is subjective, there is an unmet clinical need for fatigue biomarkers. In this explorative study, we analyzed the plasma lipidomic profiles of 47 quiescent UC and CD patients (23 fatigued, 24 nonfatigued) using ultraperformance liquid chromatography-time-of-flight mass spectrometry (UPLC-TOFMS). The results showed changes in lipids associated with fatigue and IBD. Significantly decreased levels of phosphatidylcholines, plasmanyls, sphingomyelins, lysophosphatidylcholines, phosphatidylethanolamines, phosphatidylinositols, phosphatidylserines, and eicosanoids were observed in patients with fatigue. Network and metabolic pathway analysis indicated a dysregulation of the arachidonic acid and glycerophospholipid metabolisms and the sphingolipid pathway. The protein-metabolite interaction network showed interactions between functionally related metabolites and proteins, displaying 40 disease-associated hidden proteins including ABDH4, GLTP, and LCAT.