Interferon (IFN) signaling is crucial for antiviral immunity. While Type I IFN signaling is mediated by STAT1, STAT2 and IRF9, type II IFN signaling requires only STAT1. Here, we studied the role of these signaling factors in the host response to systemic infection with Lymphocytic choriomeningitis virus (LCMV). In wild type (WT) mice and mice lacking either STAT2 or IRF9, LCMV infection was non-lethal and the virus was either cleared (WT) or established persistence (STAT2 KO and IRF9 KO). However, in the case of STAT1 KO mice, LCMV infection was lethal and accompanied by severe multi-organ immune pathology, elevated expression of various cytokine genes in tissues, and cytokines in the serum. This lethal phenotype was unaltered by the co-absence of the IFN-γ receptor and hence was not dependent on IFN-γ. Equally, this disease was not due to a combined defect in type I and type II IFN signaling as IRF9 mice lacking the IFN-γ receptor survived infection with LCMV. Clearance of LCMV is mediated normally by CD8(+) T-cells. However, the depletion of these cells in LCMV-infected STAT1 KO mice delayed, but did not prevent, lethality. By contrast, depletion of CD4(+) T-cells prevented lethality in LCMV-infected STAT1 KO mice and was associated with a reduction in tissue immune pathology. These studies highlight a fundamental difference in the role of STAT1 versus STAT2 and IRF9. While all three factors limit viral replication and spread, only STAT1 has the unique function to prevent the emergence of a lethal antiviral CD4(+) T-cell response