The role of gamma interferon (IFN-gamma) in the host response to experimental tularemia was evaluated in a murine model. C57BL/6 strain mice were given a series of daily intravenous injections of 10(6) units (U) recombinant murine IFN-gamma prior to infection with Francisella tularensis LVS. Three days later, the number of bacteria in the tissues of IFN-gamma-treated mice was found to be less than that in control mice by a factor of 10-20. The effect of IFN-gamma on anti-tularemic resistance was dependent upon the administered dose, with as little as 10(4) U/mouse/day inducing a significant level of enhanced resistance. IFN-gamma was also effective in enhancing resistance to tularemia in the A/J mouse strain which, in comparison with the C57BL/6 strain, is more susceptible to infection. When C57BL/6 mice were treated with a monoclonal antibody directed against murine IFN-gamma, the number of Francisella recovered from their tissues 6 days following infection was increased by as much as 15 times, in comparison with control mice. The results of these experiments clearly indicate that the resolution of experimental murine tularemia is dependent, at least in part, on the participation of IFN-gamma.