Interferon (IFN) was sought in simultaneously obtained samples of synovial fluid (SF) and serum from patients with a variety of rheumatological diseases. IFN was identified in 11 of 84 samples of SF and 10 of 84 specimens of serum. IFN positive specimens were contributed by patients with rheumatoid arthritis (RA), systemic lupus erythematosus, seronegative spondyloarthropathies, pseudogout, coccidioidomycosis and unclassified arthritis. Significantly, IFN was frequently found either in SF or in serum but generally not in both of the simultaneously obtained fluids. The highest titers of IFN found in SF were from patients with RA.