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Summary: Background: The advent of new therapeutic agents and the improvement of supporting care might change the management of acute severe ulcerative colitis (ASUC) and avoid colectomy. Aims: To evaluate the colectomy‐free survival and safety of a third‐line treatment in patients with ASUC refractory to intravenous steroids and who failed either infliximab or ciclosporin. Methods: Multicentre retrospective cohort study of patients with ASUC refractory to intravenous steroids who had failed infliximab or ciclosporin and received a third‐line treatment during the same hospitalisation. Patients who stopped second‐line treatment due to disease activity or adverse events (AEs) were eligible. We assessed short‐term colectomy‐free survival by logistic regression analysis. Kaplan–Meier curves and Cox regression models were used for long‐term assessment. Results: Among 78 patients, 32 received infliximab and 46 ciclosporin as second‐line rescue treatment. Third‐line treatment was infliximab in 45 (58%), ciclosporin in 17 (22%), tofacitinib in 13 (17%) and ustekinumab in 3 (3.8%). Colectomy was performed in 29 patients (37%) during follow‐up (median 21 weeks). Of the 78 patients, 32 and 18 were in clinical remission at, respectively, 12 and 52 weeks. At the last visit, 25 patients were still on third‐line rescue treatment, while 12 had stopped it due to clinical remission. AEs were reported in 26 (33%) patients. Two patients died (2.6%), including one following colectomy. Conclusion: Third‐line rescue treatment avoided colectomy in over half of the patients with ASUC and may be considered a therapeutic strategy. [ABSTRACT FROM AUTHOR]