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Introduction: Crohn's disease (CD) varies by location, potentially affecting therapy efficacy and surgery risk, although research on this topic is conflicting. This study aims to investigate the independent association between CD location and therapeutic patterns., Methods: We analyzed patients with CD diagnosed from January 2005 to May 2023 registered in the nationwide ENEIDA registry. A univariate Cox regression analysis assessed the association of disease location with biologic use and persistence (with treatment discontinuation as a failure event), as well as the use of intestinal resections. A multivariate model was constructed to evaluate the independent association of disease location with therapeutic patterns, controlling for potential confounders such as sex, age at inclusion and diagnosis, disease duration and behavior, previous surgery or biological therapy, extraintestinal manifestations, and perianal disease., Results: The study included 17,292 patients with a median follow-up period of 6 years (interquartile range 2-10 years). Ileocolonic location was associated with a higher biologic use than colonic location (hazard ratio [HR] 1.30, 95% confidence interval [CI] 1.22-1.38) and ileal disease (HR 1.21, 95% CI 1.16-1.27), independently predicting biologic use (P < 0.001). Ileal location was associated with a lower biologic persistence than ileocolonic location (HR 1.14, 95% CI 1.07-1.21) and colonic disease (HR 1.10, 95% CI 1.01-1.20), independently predicting biologic persistence (P = 0.019). Ileal disease was associated with a higher likelihood of intestinal resections than colonic (HR 2.82, 95% CI 2.45-3.25) and ileocolonic location (HR 1.13, 95% CI 1.05-1.22), independently predicting the use of surgery (P < 0.001)., Discussion: CD location with ileal predominance is associated with a distinct therapeutic pattern, including higher biologic use, lower treatment persistence, and increased rates of intestinal resections., (Copyright © 2024 by The American College of Gastroenterology.)