Purpose: To evaluate the intermediate-term safety and effectiveness of interferon alpha-2a (IFN alpha 2a) in patients with Behcet's uveitis (BU) refractory to corticosteroids and immunosuppressive agents. Design: Open, nonrandomized, uncontrolled, interventional, prospective study. Participants: Fifty-three patients (106 eyes) with active, vision-threatening BU who failed to respond to conventional treatments. Intervention: In 53 patients, acute inflammation was suppressed with effective prednisolone dosage (1-2 mg/kg/day, tapered to 10 mg within 4-6 weeks). The patients were treated with IFN alpha 2a 4.5 million international units (MIU) 3 times per week for the first 3 months followed by IFN alpha 2a 3 MIU 3 times per week for the next 3 months. Observation or other treatment methods were performed according to the decision tree developed for this study. Main Outcome Measures: Remission and complete response (primary outcome measures), frequency of uveitis attacks, visual acuity (VA), and adverse effects (secondary outcome measures). Results: During 2 years of follow-up (median 65 months, range 12-130months), compliance with the therapy was excellent. At the end of 1-year follow-up, treatment response was obtained in 45 of 53 patients (84.9%). The mean attack rate of 3.6 +/- 1.1 per year (range, 2-8) decreased to 0.56 +/- 0.75(range, 0-4) per year (P=0.001). Visual acuity improved (>= 0.2 logarithm of the minimum angle of resolution units from initial VA) in 30 eyes (28.3%) and worsened in 12 eyes (11.3%). Five patients (9.4%) did not respond to the initial treatment, and 3 patients (5.6%) developed severe adverse effects, including psoriasis, epileptic seizure, and extreme tiredness. Fifteen patients (28.3%) were off treatment for all the medications and disease free for 28 +/- 13.1 months (range, 12-50 months). Conclusions: These results suggest that IFN alpha 2a may be a valuable treatment option in BU that is refractory to corticosteroids and conventional immunosuppressive agents. The possible role of IFN alpha 2aas a first-line agent in BU should be validated in randomized controlled clinical trials against newly described biologic agents. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2010; 117: 1430-1435 (C) 2010 by the American Academy of Ophthalmology.