The effects of recombinant interferon-gamma on the production of tumor necrosis factor in 10 dairy cows with Escherichia coli mastitis were determined. Prophylactic administration of recombinant interferon-gamma prior to the experimental E. coli challenge was effective in modifying the production of endogenous tumor necrosis factor during acute stages of disease. Elevated tumor necrosis factor concentrations were especially evident in cows that developed severe clinical symptoms and eventually died from endotoxemia. These results indicate that both milk and sera tumor necrosis factor concentrations are associated closely with the manifestation of peracute signs of coliform mastitis and are important factors contributing to morbidity and mortality of endotoxic shock. Pretreatment of cows with recombinant interferon-gamma possibly may down-regulate the generation of this potent endogenous inflammatory mediator within infected quarters. Controlling severe inflammation with recombinant interferon-gamma may prevent the tremendous loss in milk production and death that often accompany acute coliform mastitis during the periparturient period.