Some, but not all, viral infections induce endogenous IL-12 to drive NK cell IFN-γ production and downstream antiviral defenses during innate immune responses. Even though lymphocytic choriomeningitis virus (LCMV) can be sensitive to IFN-γ-mediated antiviral effects, infections with this agent do not elicit IL-12 or early IFN-γ in immunocompetent hosts. Studies presented here demonstrate that LCMV infections of mice not only fail to induce IL-12, but also modify responsiveness to exogenous IL-12 for IFN-γ production. IFN-γ responses induced by IL-12 administration were greatly diminished in splenic populations, but significantly increased in serum and hepatic leukocytes, during the early course of LCMV infections. The IFN-γ production was NK cell dependent, and the compartmental dichotomy between spleen and liver was also demonstrated in response to in vitro IL-12 stimulation. Although infections did increase proportions and numbers of liver NK cells, changes in responsiveness for IFN-γ expression could not be explained by cell redistribution. Corroborating changes in proportions of NK cells induced to express intracellular IFN-γ protein within the compartments were observed. The reduction in ability of splenic populations to produce IL-12-induced IFN-γ after infection by LCMV was associated with decreased efficacy of administered IL-12 for promoting IFN-γ-dependent antiviral effects in the spleen. Concomitantly, the maintenance of hepatic population IFN-γ production was associated with preserved efficacy of administered IL-12 to elicit IFN-γ-dependent antiviral effects in the liver. Taken together, these results demonstrate modifications of compartmental responses to IL-12 by viral infections and the consequences of these changes for efficacy of cytokine therapy.