Interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) are proinflammatory cytokines which may be involved in the pathogenesis of MS. IFN-alpha counteracts many of the proinflammatory actions of IFN-gamma and TNF-alpha. We treated 20 patients with relapsing-remitting (RR) MS with 9 MIU of recombinant IFN-alpha-2a (rIFN-alpha) (n = 12) or placebo (n = 8) intramuscularly every other day for 6 months. Clinical exacerbations or new or enlarging lesions at serial MRI occurred in 2/12 rIFN-alpha-treated and in 7/8 placebo-treated patients (P < 0.005). Only one new MRI lesion was detected in the rIFN-alpha group, while 27 new or enlarging lesions were detected in placebo group (P < 0.01). Baseline lymphocyte IFN-gamma (19.10 +/- 7.12 U ml-1) and TNF-alpha (18.05 +/- 5.34 pg ml-1) production significantly decreased to 3.03 +/- 0.66 (P < 0.04) (for IFN-gamma) and to 5.78 +/- 0.90 (P < 0.04) (for TNF-alpha) after rIFN-alpha treatment. IFN-gamma and TNF-alpha production was unchanged in the placebo group. rIFN-alpha was tolerated without drop-outs or serious side-effects, but fever, malaise, fatigue (interfering with daily activities in two patients) and leukopenia frequently occurred. High-dose chronic systemic rIFN-alpha might reduce clinical and MRI signs of disease activity in RRMS. The changes in cytokine production suggest that the effect is probably mediated by a down-regulation of proinflammatory cytokine.