We inoculated BALB/c mice deficient in STAT6 (STAT6(-/-)) and their wild-type (wt) littermates (STAT6(+/+)) with the natural mouse pathogen, ectromelia virus (EV). STAT6(-/-) mice exhibited increased resistance to generalized infection with EV when compared with STAT6(+/+) mice. In the spleens and lymph nodes of STAT6(-/-) mice, T helper 1 (Th1) cytokines were induced at earlier time points and at higher levels postinfection when compared with those in STAT6(+/+) mice. Elevated levels of NO were evident in plasma and splenocyte cultures of EV-infected STAT6(-/-) mice in comparison with STAT6(+/+) mice. The induction of high levels of Th1 cytokines in the mutant mice correlated with a strong natural killer cell response. We demonstrate in genetically susceptible BALB/c mice that the STAT6 locus is critical for progression of EV infection. Furthermore, in the absence of this transcription factor, the immune system defaults toward a protective Th1-like response, conferring pronounced resistance to EV infection and disease progression.