Background: Patients with inflammatory bowel disease who are refractory to standard therapies frequently require surgery. The long-term efficacy of tacrolimus in patients who fail standard immunosuppressive and antitumor necrosis factor α therapy is unknown. Methods: Thirty-five patients (11 Crohn's disease and 24 ulcerative colitis) with medication-resistant disease were treated with oral tacrolimus and reviewed retrospectively. Patients were commenced on tacrolimus 0.1 mg/kg/day, with a trough level targeted between 8 and 12 ng/mL. Clinical response or remission at 30 days, 90 days, and 1 year was assessed. The overall risk of requiring surgery and predictive factors were also assessed. Results: All patients had failed a thiopurine, 5 (14%) had also failed methotrexate, while 90% had a primary or secondary nonresponse, or an incomplete response, to an antitumor necrosis factor a agent. The proportions that achieved a clinical response at 30 days, 90 days, and 1 year was 65.7%, 60%, and 31.4%, respectively, whereas the corresponding proportions in remission were 40%, 37.1%, and 22.9%. The cumulative risk of requiring surgery was 40.4% at 1 year and 59.3% at 2 years with a median time to surgery of 22 months (range, 0.5-84 months). Patients who were steroid refractory, or dependent, before starting tacrolimus were more likely to have surgery (P = 0.006), whereas patients who were able to achieve or maintain a clinical response with tacrolimus by 90 days were less likely (P = 0.004). Conclusions: Tacrolimus is able to induce a clinical response in a third and remission in a fifth of medically refractory patients with inflammatory bowel disease at 1 year. A 90-day therapeutic trial is worthwhile in difficult to treat patients. Copyright © 2013 Crohn's and Colitis Foundation of America, Inc.