BACKGROUND: Lifestyle factors are significant contributors to fatigue, affecting ~45% of patients with inflammatory bowel disease (IBD). Hence, we evaluated the effect of a multimodal lifestyle intervention on fatigue in patients with IBD. METHODS: Patients with quiescent IBD were enrolled in this multicenter, non-randomized, controlled interventional study. The intervention group followed a 12-month lifestyle program, which included digital group meetings with a nutritionist and a lifestyle coach focusing on nutrition, exercise, sleep, and relaxation. The program also encouraged patients to exercise more self-control over personal health. The control group received standard clinical care. Clinical data and patient-reported outcomes were collected. Fatigue was measured with the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F); any increase in FACIT-F was considered a positive response to the intervention. Inverse probability treatment weighting was used to correct confounding by indication. RESULTS: Thirty-six patients in the intervention group and 32 in the control group were compared. More patients in the intervention group (82.1%) than in the control group (54.2%) experienced improvement in fatigue, P = .029, standardized mean difference (SMD) -0.624. Over 70% of patients in the intervention group achieved a clinically relevant improvement in fatigue. Compared to the control group, quality of life improved in the intervention group. Acceptance of the health status was a significant factor for fatigue improvement (beta = 7.899, SE = 1.913, P < .001). CONCLUSIONS: Multimodal lifestyle intervention improves fatigue in patients with IBD. Acceptance appears essential for fatigue improvement; instruments evaluating acceptance could help to personalize treatment and maximize its effectiveness.