Circulating interleukin-6 (IL-6) levels are directly correlated to fatal outcome in both patients and animal models with endotoxin shock. However, whether IL-6 is deleterious or protective in regard to survival is obscure. We investigated the action of IL-6 in the pathogenic progress of endotoxin shock. C3H/HeN mice received 10 micrograms of natural human IL-6 (Hu-IL-6) s.c. at various times before or after challenge with Escherichia coli lipopolysaccharide (LPS) at a lethal dose. Pretreatment with Hu-IL-6 0, 1, and 4 h before LPS administration improved the survival rate of the mice. However, no protection was observed when Hu-IL-6 was administered 24 h before or 1 h after the LPS injection. The protective mechanism of Hu-IL-6 pretreatment was not explained on the changes in the circulating levels of tumor necrosis factor and endogenous murine IL-6 (Mu-IL-6). The induction of fibrinogen and immunosuppressive acidic protein, a type of acute-phase proteins, may have contributed to the protection. The results show that the order and the time interval in which the administered Hu-IL-6 and the Mu-IL-6 induced by LPS act are the key to the determination of fatal outcome.