INTRODUCTION: Patients with moderate-to-severe ulcerative colitis (UC) who are steroid-dependent despite being on immunomodulators pose significant clinical challenges. Currently, biologics therapy is the only option apart from considering surgery. Tofacitinib is an oral Janus kinase inhibitor used as a second-line therapy for patients with UC following the failure of biologics therapy. There is a lack of Indian data on the use of tofacitinib in biologically naive patients with moderate-to-severe UC. Our study aimed to evaluate the efficacy and safety of tofacitinib in steroid-dependent patients with moderate-to-severe UC who were already on immunomodulators. MATERIALS AND METHODS: An open-label, single-arm, prospective observational study was conducted on steroid-dependent UC patients from January 2021 to June 2023. All eligible patients received tofacitinib according to standard guidelines. Clinical response and remission were assessed at eight and 24 weeks. RESULTS: A total of 53 patients met the inclusion criteria, of whom 52.83% were male and 47.16% were female. The mean age was 40.35 years (SD +/- 10.85 years). At eight weeks, 36 patients (67.92%) showed a clinical response, 19 (35.8%) achieved clinical remission, and 12 (22.64%) attained endoscopic remission. At 24 weeks, 35 patients (66.03%) achieved clinical remission (p<0.001), and 22 (41.50%) attained endoscopic remission (p=0.003). A total of 36 patients (68%) showed a clinical response, while 17 (32%) did not respond to tofacitinib at eight weeks. CRP and Mayo scores showed significant differences between responders and non-responders (p<0.001). Only two patients developed herpes zoster infection, both of whom were managed conservatively without requiring discontinuation of tofacitinib. No other adverse effects, such as thromboembolic events, were observed during the study period. CONCLUSION: The oral small-molecule tofacitinib is an effective and safe treatment for moderate-to-severe UC that is steroid-dependent in patients already on immunomodulators.