Objective: Behçet disease (BD) is a multisystem vasculitis of unknown origin. Standard treatment mainly comprises systemic immunosuppressive agents. In a study primarily designed for refractory ocular disease, we additionally evaluated the efficacy of recombinant human interferon-α2a (rhIFN-α2a) on the extraocular manifestations of BD. Methods: Fifty patients were included in the study. RhIFN-α2a was applied at a dose of 6 × 106 units subcutaneously daily. Dose reduction was performed according to a decision tree until discontinuation. Disease activity was evaluated by the Behçet's Disease Activity Scoring System and the Uveitis Scoring System. Results: Response rate of the ocular manifestations was 92%. Visual acuity rose significantly from 0.56 to 0.84 at week 24 (P < .0001). Mean Behçet's Disease Activity Score fell in a dose-dependent fashion by 1.2 points in the first week (P < .0001) and from 5.8 to 3.3 at week 24 and further to 2.8 at week 52. After a mean observation period of 36.4 months, 17 patients have been off treatment and disease-free for 29.5 months (mean). In the other patients, maintenance IFN dosage is 3 million units 3 times weekly. Whereas extraocular manifestations such as genital ulcerations, arthritis, and skin lesions remitted with IFN, only 36% of oral aphthous ulcers responded. Conclusions: RhIFN-α2a is effective in ocular BD, resulting in significant improvement of vision and complete remission of ocular vasculitis in the majority of patients. It is also beneficial for the extraocular manifestations of the disease, although less so for oral aphthous ulcers.