The effect of simvastatin applied in a short-term pretreatment on proinflammatory cytokines production in acute systemic inflammation induced by endotoxin - lipopolysaccharide (LPS) in rats was investigated. Both LPS and simvastatin doses were established in separate experiments in which increasing doses of both compounds were given to obtain the LD(50) LPS and the maximally protective dose of simvastatin against LD(50) LPS. To determine the anti-inflammatory effect, simvastatin was given orally for 5 days, followed by a single intraperitoneal non-lethal dose of LPS (0.25 LD(50)). Plasma concentrations of tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta and IL-6 were measured by enzyme-linked immunosorbent assay. The acute i.p. LD(50) LPS amounted to 22.15 mg/kg. Simvastatin of 20 mg/kg p.o. was maximally protective against LD(50) LPS, and this dose was used for studying its effects on LPS-induced cytokines production. Cytokines concentrations were significantly increased upon challenge of non-lethal dose of LPS. The peak levels of TNF-alpha and IL-1beta were significantly suppressed by simvastatin, compared to control rats only treated with dimethylsulfoxide before LPS. In contrast, simvastatin did not affect IL-6 levels at all timepoints. Simvastatin pretreatment given orally produced acute anti-inflammatory effects by inhibiting TNF-alpha and IL-1beta, but no IL-6 production.