Interferons are natural glycoproteins that have antiviral, antiproliferative and immune regulatory functions. They are not only involved in the pathogenesis of certain autoimmune conditions but are also useful in the treatment of some rheumatologic disorders, notably Behçet's syndrome. Interferon alpha (IFNalpha) has been recommended for severe eye involvement in Behçet's syndrome, especially when there is a significant drop in visual acuity and/or retinal involvement. It can induce a high rate of complete remission that may also persist after its discontinuation. When given early at the beginning, interferon might be effective in ameliorating the attacks of familial Mediterranean fever resistant to colchicine treatment. The combination of PEGylated IFNalpha with ribavirin and rituximab emerges as a novel and promising treatment providing complete clinical response and viral clearance in hepatitis C virus-associated mixed cryoglobulinemia. Limited data also suggest that interferon may induce remissions in Churg-Strauss patients who fail to respond to conventional immunosuppressive treatment. Among several rheumatologic diseases, IFNalpha has found more widespread use in Behçet's syndrome and hepatitis C virus-associated mixed cryoglobulinemia despite a paucity of formal studies. Patients should be carefully monitored for the frequent and dose-dependent adverse effects.