Interferon (IFN) -system of patients with multiple sclerosis (MS) during the stable stage of the disease activity was investigated. Thirty six patients were divided into 3 groups of mild, moderate and severe patients according to the scores of disability status scale (DSS). IFN-alpha producibility and natural killer (NK) activity of peripheral blood lymphocytes (PBL) or large granular lymphocytes (LGL) fractionated from PBL were determined by culturing with HeLa cells persistently infected with measles virus (HeLa/MV) and K562 cells. IFN-gamma was induced in PBL obtained from the patients using killed cells of Propionibacterium acnes (P. acnes), Listeria monocytogenes (LM) and Streptococcus salivarius (Str. sal.) and a lectin of concanavalin A (Con A). Both IFN-alpha producibility and NK activity of PBL obtained from the patients were depressed in parallel with the severity of DSS of the patients. The depressed NK activity of the patients could be recovered by neither IFN-alpha nor interleukin-2 added exogenously. In addition, the induction of IFN-gamma was also depressed in the patients in response to P. acnes and LM, but not Str. sal. or Con A. These results suggest that the defect of IFN-system observed in PBL of the patients may result from the depressed function of both LGL and T lymphocyte subpopulations which are responsive to P. acnes and LM. It is postulated that these immunocompetent cells might migrate to subclinical demyelinating lesions of central nervous system where cytokines including IFN-gamma were produced locally, and that their migration might result in the quantitative decrease of lymphocytes participating in IFN-system in PBL of patients with MS.