Abstract Title Double Trouble in the Gut: Unraveling the Tangled Tale of Eosinophilic Esophagitis and Inflammatory Bowel Disease Background Eosinophilic esophagitis (EoE) and inflammatory bowel disease (IBD) are both immunologically mediated gastrointestinal disorders. While previous studies have suggested a possible association between these conditions, results have been inconsistent. Methods We conducted a retrospective cohort study using the TriNetX database, examining IBD patients from 2013 to 2022. We stratified the data by type of IBD, age, sex, and race to assess the incidence and risk factors of EoE in patients with IBD. Additionally, we evaluated the 5-year clinical outcomes of patients with concurrent EoE and IBD compared to those with either condition alone. Propensity score matching was performed for age, sex, race, BMI, smoking, PSC, steroid use, other autoimmune diseases, IBD medications, and surgery history. Risk was quantified using adjusted odds ratios (aOR) with 95% confidence intervals (CI). Results Among 234,582 patients with IBD (mean age 45.4, female sex 52.5%, White race 74.8%, CD 52.8%), the risk of EoE was higher in the IBD cohort (aOR: 2.88, CI: 2.59-3.19) compared to the non-IBD cohort. Following subgroup analysis in the UC cohort, younger age (<40) and male sex were associated with a higher risk of EoE, while in the CD cohort, younger age, male sex, obesity, and history of CD-related surgery were significant risk factors. For the clinical outcomes study, 853 patients with UC and EoE and 1,162 with CD and EoE were matched with control cohorts. The UC-EoE cohort showed an increased risk of IV steroid use (aOR: 1.46, CI: 1.19-1.79) but no difference in oral steroid use, advanced therapy initiation, or colectomy. The CD-EoE cohort demonstrated higher risks of IV steroid use, advanced therapy use, and PSC, with no significant difference in colectomy rates. In another analysis of 887 patients with EoE and IBD, the EoE-IBD cohort exhibited a lower risk of a composite outcome of esophageal dilation and/or Dupilumab use (aOR: 0.39, CI: 0.29-0.52), with no difference in esophageal dilations alone or food impactions. Conclusion Our study reveals a roughly threefold increased risk of EoE in patients with IBD. Additionally, patients with coexisting EoE and IBD experience worse clinical outcomes, particularly those with CD, highlighting the need for close outpatient monitoring and follow-up. Interestingly, patients with EoE and IBD may benefit from immune-modifying therapies used for IBD, resulting in more favorable outcomes compared to those with EoE alone.