OBJECTIVE To compare the effect of oral and IV administrations of flunixin meglumine on the endotoxin-induced inflammatory response in heifers. METHODS The study was conducted in 2 experimental sets in which heifers were exposed to low IV doses of Escherichia coli endotoxin. Within each set, heifers were allocated to 3 treatment groups; pretreatment with flunixin meglumine orally and IV prior to endotoxin administration, or endotoxin administration only. The dose of flunixin used was the recommended therapeutic dose in cattle. METHODS 11 clinically normal heifers weighing from 400 to 640 kg. METHODS A permanent cannula was inserted into the jugular vein on the day prior to the experiment. Blood samples were collected regularly during the experiment and analyzed for the content of prostaglandin F2 alpha metabolite, cortisol, blood mononuclear cells, and polymorphonuclear neutrophilic leukocytes and rectal temperature was measured. RESULTS Endotoxin administration caused clinical signs and hematologic changes characteristic of endotoxemia in cattle. Flunixin administered orally prior to experimentally induced endotoxemia exerted an effect equal to that after its IV administration. Significant increases in rectal temperature and prostaglandin F2 alpha metabolite concentrations after administration of endotoxin were abrogated when the heifers were pretreated with flunixin, irrespective of route of administration. Cortisol concentrations were lower after pretreatment with flunixin. However, flunixin did not prevent the decrease in blood mononuclear cells and polymorphonuclear neutrophilic leukocytes seen after endotoxin administration. CONCLUSIONS Owing to no major difference in the inflammatory response between oral and IV flunixin dosing, flunixin granules may be an alternative to parenteral use in bovine practice.