GOALS: This analysis compared the real-world effectiveness and safety of vedolizumab versus ustekinumab in biologic-naive patients by CD location. BACKGROUND: Crohn's disease (CD) location may affect disease course and treatment decisions. STUDY: Medical charts of biologic-naive patients with CD aged 18 years or older initiating vedolizumab or ustekinumab were analyzed in the multicenter, observational, retrospective EVOLVE Expansion study. Outcomes with vedolizumab versus ustekinumab over 36 months were compared in patients with baseline isolated ileal, ileocolonic, and isolated colonic CD (Montreal classification). RESULTS: This analysis included 293 patients with ileal (vedolizumab, n=158, ustekinumab, n=135), 185 with ileocolonic (vedolizumab, n=91, ustekinumab, n=94), and 121 with colonic (vedolizumab, n=84, ustekinumab, n=37) CD. Cumulative rates over 36 months were similar between vedolizumab and ustekinumab in ileal, ileocolonic, and colonic CD subgroups for clinical response, remission, mucosal healing, and treatment persistence. There were no differences in risks of serious adverse events, serious infections, CD exacerbations, and CD-related hospitalizations between cohorts across disease location; the risk of CD-related surgeries was similar in patients with ileocolonic and colonic CD, and higher with vedolizumab versus ustekinumab in patients with ileal CD. CD-related surgeries for ileal CD were reported in 12 of 158 (7.6%) vedolizumab-treated patients and 3 of 135 (2.2%) ustekinumab-treated patients. CONCLUSIONS: Effectiveness, safety, and health care resource utilization outcomes over 36 months were similar between treatment cohorts regardless of baseline disease location. The number of patients requiring CD-related surgeries was low. Both vedolizumab and ustekinumab can be used as first-line biologics in patients with CD, regardless of disease location.