We have demonstrated the effectiveness and safety of combining cyclosporine and vedolizumab to treat ulcerative colitis (UC). We present 2 cases of hospitalized acute severe UC who had failed therapy with antitumor necrosis factor and vedolizumab and were treated successfully with induction cyclosporine and safely bridged to ustekinumab maintenance therapy. Both patients have avoided colectomy. There were no adverse events. We propose this novel treatment combination in medically resistant acute severe UC.