Objective. In Behçet's disease (BD), several abnormalities of lymphocyte subpopulations have been described. Standard treatment comprises immunosuppressive drugs. We successfully treated 50 patients with ocular BD with interferon-α2a (IFN-α2a) (response rate 92%), although this is counterintuitive because IFN-α is immunostimulatory and can sometimes even induce autoimmune diseases such as systemic lupus erythematosus or rheumatoid arthritis. The aim of the present study was to elucidate the immunomodulatory effects that IFN-α might exert on peripheral blood mononuclear cells (PBMC) in BD by examining changes in the distribution of lymphocyte subpopulations under IFN-α2a treatment. Methods. Fourteen patients with ocular BD were evaluated before and at weeks 4 and 24 of IFN-α treatment and compared with 10 healthy controls. PBMC were stained with monoclonal antibodies and measured by flow cytometry. Results. Compared with the controls there is a significant elevation of monocytes (CD14+), CD8+/γδ T cells, CD3+/γδ T cells, natural killer (NK) cells (CD56+/CD16+) and activated/regulatory T cells (CD4+/CD25+ and CD8+/CD25+) in patients with active BD before treatment with IFN-α2a. Numbers of naïve T cells (CD8+/CD45+RA+/RO-, CD4+/CD45+RA+/RO-) were significantly lower. Under therapy, NK cells, CD8+/γδ T cells and CD3+/γδ T cells decreased significantly, whereas B cells increased. The previously reduced expression of HLA class I on monocytes in HLA-B51-positive patients rose to levels comparable to HLA-B51-negative patients. Conclusion. These results implicate the participation of NK cells and γδ T cells, especially CD8+/γ δ T cells, in the pathogenesis of BD and may explain one mechanism by which IFN-α2a exerts therapeutic effects. Alternatively, they may result indirectly from remission induction by IFN-α2a. The reduced expression of HLA class I on monocytes in HLA-B51-positive patients might reflect an impaired expression of and antigen presentation by HLA-B51.