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Background: A healthy lifestyle, including good adherence to a Mediterranean diet (MD) and regular physical exercise, may be an important factor during the course of inflammatory bowel disease (IBD). Our aim is to determine whether adherence to MD, physical activity, and the combination of both can impact on IBD course., Methods: This prospective cohort study includes 693 IBD outpatients who were in remission with a median follow-up time of 27 months (interquartile range 22-29 months). Each patient completed a survey to assess their adherence to the MD and physical activity. Healthy lifestyle was considered to be a proper adherence to both MD and an active lifestyle. Relapse during follow-up, severity of relapses, need for systemic steroids, and therapy changes were recorded., Results: During the follow-up period, 188 patients (27.1%) experienced relapse, of which 56.1% were moderate or severe. Among patients with relapse, 85 (45%) required treatment with corticosteroids, and 15 (7.9%) were hospitalized. Patients with ulcerative colitis (CU) were more adherent to healthy lifestyle than patients with Crohn's disease (P = .011). Healthy lifestyle was associated with lower risk of moderate and severe relapses (adjusted Hazard ratio [aHR], 0.250; 95% confidence interval [CI], 0.093-0.670) and steroids use (aHR 0.292; 95% CI, 0.103-0.828) in IBD patients and with lower risk of moderate and severe relapses (aHR 0.270; 95% CI, 0.093-0.789) in UC patients., Conclusions: Healthy lifestyle has a favorable influence on promoting a milder disease course, and thus should be a crucial part of clinical management of patients with IBD., (© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)