BACKGROUND: Ciclosporin and infliximab have equal short-term efficacy in treating acute severe ulcerative colitis (ASUC). However, data about long-term outcome and switching to a second rescue therapy are limited. METHODS: Patients with steroid-refractory ASUC treated at a tertiary center in Switzerland were retrospectively analyzed regarding the outcome of different rescue therapies. Colectomy-free survival rates at 1, 3, and 5 years were estimated through Kaplan-Meier method. Furthermore, predictors of colectomy, the presence of adverse events at 1 year and mortality during the entire follow-up were assessed. RESULTS: We analyzed a total of 46 patients who were treated initially with either ciclosporin (n = 31) or infliximab (n = 15) due to steroid-refractory ASUC between January 2010 and July 2021. A total of 13% patients received a second rescue therapy. In sum, 78%, 67%, and 48% were colectomy-free at 1, 3, and 5 years, respectively. Although there was a significant difference between the three arms in colectomy-free survival (p = 0.026), a post hoc analysis could not demonstrate a difference between each individual therapy compared to another. The post hoc analysis indicated a nonsignificant benefit with sequential therapy in comparison to ciclosporin (CsA) regarding the colectomy-free survival (p = 0.087). The outcome between infliximab and CsA was not statistically different (p = 0.149). The number of previous advanced therapies was negatively associated with 1-year colectomy-free survival (p = 0.049). Other variables such as age at hospitalization, sex, dose of steroids, disease duration, and albumin did not correlate with a higher risk of 1-year colectomy. CONCLUSIONS: This real-world single-center analysis confirms the equal efficacy and safety of infliximab and ciclosporin over a follow-up of 5 years. Patients not responding to the first may benefit of a second rescue therapy without increasing the risk of complication or mortality.