OBJECTIVE: Ulcerative colitis (UC) is a chronic immune-mediated disease requiring ongoing treatment to maintain remission. This report presents the 2-year safety outcomes of mirikizumab, a humanized immunoglobulin G4 anti-interleukin-23p19 monoclonal antibody, in moderately to severely active UC from Phase 3 studies LUCENT-1 (NCT03518086), LUCENT-2 (NCT03524092), and LUCENT-3 (NCT03519945). METHODS: Patients who underwent induction (LUCENT-1) and maintenance (LUCENT-2), and entered long-term maintenance (LUCENT-3) were assessed in 2 cohorts: induction responders and extended-induction responders. Both cohorts underwent up to 104 weeks of continuous treatment with mirikizumab. Adverse events (AEs) were assessed in these 2 cohorts and within subsets of patients aged ≥60 years and patients using corticosteroids, immunomodulators, or both at baseline. RESULTS: Safety was generally consistent across induction responders (N=333) and extended-induction responders (N=149) and across patient subsets. Nasopharyngitis, COVID-19, arthralgia, UC (worsening/reoccurrence of symptoms), and headache were the most common AEs. Serious AEs were reported in less than 10% of both cohorts. Infections (mostly mild), cerebrocardiovascular events, and malignancies occurred, respectively, in 47.4% and 49.7%, 0.9% and 1.3%, and 0% and 3.4% of induction responders and extended-induction responders. Injection-site reactions (induction responders: 10.2% and extended-induction responders: 8.1%) declined over time. Safety profiles in patient subsets and in the whole population were similar, except for hypertension, which was more frequent in patients aged ≥60 years. CONCLUSIONS: The mirikizumab 2-year integrated safety profile in patients with moderately to severely active UC was consistent across subgroups and with previous findings, without new significant safety concerns.