In a prospective, placebo-controlled study designed to test the efficacy of human alpha interferon (IFN) in the treatment of multiple sclerosis, we monitored several immunological functions. Interferon was shown to have many effects on the immune system, including activation of natural killer cells in vivo and elevation of serum immunoglobulin and cerebrospinal fluid IgG ratios. Furthermore, all patients who received IFN developed antibody titers to a protein contaminant (molecular weight, 27 kilodaltons) in the IFN preparation. This antibody was associated with an elevation in serum concentrations of C1q- and Raji-binding immune complexes in 6 of 12 patients. Some of these 12 patients developed symptoms suggestive of immune complex disease. IFN had pronounced effects on the immune system of these patients.