We investigated short-term alterations in plasma interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor α (TNF-α) levels induced by interferon alfa (IFN-α) injection in 18 patients with chronic hepatitis C. A single intramuscular injection of human recombinant IFN-α 2a (6 million units [MU]) significantly increased the plasma IL-6 level 6 hours after the injection (P < .05). On the other hand, the IFN-α injection did not affect the plasma TNF-α and IL-lβ levels. Polymerase chain reaction (PCR) analysis showed accumulation of IL-6 gene transcripts in peripheral blood mononuclear cells (PBMC) after IFN-α injection, indicating that IFN-α enhances IL-6 production at the messenger RNA level. The induction of IL-6 by IFN-α was completely suppressed by the intravenous administration of gabexate mesilate (GM), a serine protease inhibitor. The mechanism whereby GM suppresses the elevation in circulating IL-6 levels seems to be the inhibition of IL-6 production at the messenger RNA level. Elevations of both serum C-reactive protein (CRP) levels and body temperature after GM-suppressed IFN-α injection suggest that the administration of GM by suppressing IL-6 production, may attenuate the IL-6-related responses induced by IFN-α injection. In conclusion, we found that IL-6 was induced by IFN-α in vivo, and that this induction was completely abrogated by the administration of GM. Our results indicate that serine protease inhibitors may be useful for inhibiting IL-6-relating responses.