The pathogenesis of inflammatory bowel disease (IBD) has not been fully uncovered to date. Epstein-Barr-Virus (EBV) infection has recently been associated with the pathogenesis of multiple sclerosis, suggesting a general link between EBV and autoimmune diseases. However, data on an association between EBV and IBD have remained inconclusive. This study aims at evaluating an association between EBV and the development of IBD.

This retrospective cohort study included 15 931 patients with and 15 931 matched patients without infectious mononucleosis from the Disease Analyzer database (IQVIA) between 2000 and 2018. Incidences of Crohn’s disease and ulcerative colitis were evaluated using Cox regression models.

Within 5 years of the index date, the cumulative incidence of IBD was 124 and 90 cases per 100 000 person-years among patients with and without infectious mononucleosis, respectively (P = 0.040). In regression analyses, infectious mononucleosis was significantly associated with IBD [hazard ratios (HR), 1.35; 95% confidence interval (CI), 1.01–1.81]. Subgroup analyses revealed an association between infectious mononucleosis and Crohn’s disease (HR, 1.93; 95% CI, 1.22–3.05) but not ulcerative colitis (HR, 1.03; 95% CI, 0.70–1.51). This association was strongest in patients between 14 and 20 years (HR, 4.50; 95% CI, 1.55–13.13) and was only observed in females (HR, 2.51; 95% CI, 1.39–4.53).

Infectious mononucleosis is significantly associated with an increased incidence of Crohn’s disease but not ulcerative colitis, especially in young female patients. Our data support the hypothesis of a pathophysiological involvement of EBV in the development of Crohn’s disease and should trigger molecular research to further dissect the pathophysiology of IBD.