Using a model of endotoxemia triggered by the intravenous injection of bacterial lipopolysaccharide (0.1 and 1 mg/kg) to guinea-pigs, we investigated the interference of fenspiride, an anti-inflammatory drug recommended for the treatment of inflammatory diseases of the upper respiratory tract. Administered orally at 60 mg/kg, fenspiride reduced the lipopolysaccharide-induced early rise of tumor necrosis factor concentrations in serum (4.2 ± 0.9 vs. 2.3 ± 0.5 ng/ml, P < 0.05) and in the bronchoalveolar lavage fluid (55.7 ± 20 vs. 19.7 ± 7.5 ng/ml, P < 0.05). The lipopolysaccharide-induced primed stimulation of alveolar macrophages, defined as their enhanced release of arachidonic acid metabolites as compared to cells from untreated controls upon stimulation with N-formyl-methionyl-phenylalanine was also reduced by fenspiride (1551.5 ± 183.7 vs. 771.5 ± 237.5 pg/μg protein, P < 0.05 for thromboxane B₂ and 12.6 ± 4.9 vs. 3.6 ± 0.9 pg/μg protein, P < 0.05 for leukotriene C₄). Finally, fenspiride reduced the increased serum concentrations of extracellular type II phospholipase A₂ (3.9 ± 1.2 vs. 1.2 ± 0.1 nmol/ml per min, P < 0.01), the intensity of the neutrophilic alveolar invasion and the lethality due to the lipopolysaccharide. The protective effect of fenspiride may result from the inhibition of the formation of tumor necrosis factor, a major mediator of the effects of lipopolysaccharide.