Background <p>Recent studies have established a role for Janus kinase (JAK) inhibitors in the management of patients with inflammatory bowel disease. However, these studies excluded patients with an ileostomy.</p> Aim <p>We sought to evaluate the clinical response of patients with Crohn’s disease (CD) and ileostomy who were treated with upadacitinib.</p> Methods <p>This retrospective study included patients with CD who had an ileostomy secondary to medically refractory CD and who were treated with upadacitinib. Patients who underwent ileostomy takedown and continued taking upadacitinib were analyzed separately from patients with an ileostomy throughout upadacitinib treatment duration. The primary endpoint was clinical response defined by either continuation or discontinuation of upadacitinib. The secondary endpoint was identifying variables that lead to discontinuation of upadacitinib.</p> Results <p>A total of 48 patients, between the ages of 17–70&#xa0;years met our inclusion criteria of having CD, an ileostomy, and upadacitinib use after ileostomy creation. Of the 48 patients, 32 (67%) had clinical improvement in CD activity with upadacitinib use based on review of clinical documentation. Upadacitinib was discontinued in 16 patients (33%) for various reasons including refractory symptoms related to CD, deep vein thrombosis, anemia/leukopenia, insurance denial, pregnancy planning, headache/back pain, or squamous cell carcinoma of the skin.</p> Conclusion <p>We evaluated the efficacy of upadacitinib in patients with CD and ileostomy. Two-thirds of our cohort experienced improvement in CD-related symptoms with upadacitinib use. Further studies are needed to evaluate if altered gastrointestinal anatomy significantly impacts absorption and efficacy of upadacitinib in patients with CD.</p>