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Aim: To address the management of Clostridium difficile ( C. difficile ) infection (CDI) in the setting of suspected inflammatory bowel disease (IBD)-flare., Methods: A systematic search of the Ovid MEDLINE and EMBASE databases by independent reviewers identified 70 articles including a total of 932141 IBD patients or IBD-related hospitalizations., Results: In those with IBD, CDI is associated with increased morbidity, including subsequent escalation in IBD medical therapy, urgent colectomy and increased hospitalization, as well as excess mortality. Vancomycin-containing regimens are effective first-line therapies for CDI in IBD inpatients. No prospective data exists with regards to the safety or efficacy of initiating or maintaining corticosteroid, immunomodulator, or biologic therapy to treat IBD in the setting of CDI. Corticosteroid use is a risk factor for the development of CDI, while immunomodulators and biologics are not., Conclusion: Strong recommendations regarding when to initiate IBD specific therapy in those with CDI are precluded by a lack of evidence. However, based on expert opinion and observational data, initiation or resumption of immunosuppressive therapy after 48-72 h of targeted antibiotic treatment for CDI may be considered., Competing Interests: Conflict-of-interest statement: D’Aoust J and Battat R confirm that there are no conflicts of interest to declare; Bessissow T has received fees as a speaker for Janssen, Shire, Abbvie, Takeda, Ferring, and Pendopharma; Bessissow T has a research grant from Abbvie, Janssen; Bessissow T has consulted for Abbvie, Takeda, Shire.