BACKGROUND & AIMS: The efficacy and safety of extended treatment with risankizumab (RZB), an anti-interleukin-23 p19 monoclonal antibody, were evaluated in patients with moderate to severe Crohn's disease (CD) who did not achieve clinical response to 12 weeks (W) RZB induction treatment ('initial nonresponders'). METHODS: Initial nonresponders to intravenous (IV) RZB induction (600 mg or 1200 mg at W0, W4, and W8) were rerandomized 1:1:1 to receive extended blinded RZB treatment (1200 mg IV at W12, W16, and W20, or subcutaneous [SC] 180 mg or 360 mg at W12 and W20). Patients with clinical response to SC RZB at W24 ('delayed responders') continued their dose in FORTIFY. Clinical, endoscopic, and safety outcomes were evaluated. RESULTS: Most initial nonresponders achieved stool frequency (SF)/ abdominal pain score (APS) clinical response by W24 (76.2% [180 mg SC], 63.7% [360 mg SC], 62.3% [1200 mg IV]), whereas a subset also achieved W24 SF/APS clinical remission (43.0%, 45.1%, and 22.1%), endoscopic response (32.4%, 32.5%, and 40.5%), and endoscopic remission (25.1%, 18.0%, and 23.5%). Most delayed responders to SC RZB continued to demonstrate clinical response at FORTIFY W52 (56.7% [180 mg SC], 69.7% [360 mg SC]), along with SF/APS clinical remission (43.3% and 54.5%), endoscopic response (36.7% and 45.5%), and endoscopic remission (40.0% and 42.4%). Numerically greater efficacy was generally observed with 360 mg SC vs 180 mg SC. The safety profile of extended treatment was consistent with previously reported trials. CONCLUSION: Most initial nonresponders to IV RZB induction who received 12W of extended RZB treatment demonstrated improved clinical and endoscopic outcomes at W24. Improvements in patients who received SC RZB extended treatment were maintained during FORTIFY. Extended treatment was well tolerated with no new safety risks identified. CLINICALTRIALS: gov: MOTIVATE (Number: NCT03104413), ADVANCE (Number: NCT03105128), and FORTIFY (Number: NCT03105102).