Host immune response influences development of life-threatening influenza infection in healthy individuals. We previously reported that in children admitted to the intensive care unit (ICU) with influenza, early Toll-like receptor 4 (TLR4) pathway suppression with ex vivo lipopolysaccharide (LPS) stimulation (low tumor necrosis factor (TNF)α production), predicted higher mortality. In an independent cohort of 105 influenza infected children enrolled across 24 PICFLU Study ICUs, we evaluated immunosuppression of the viral-specific retinoic acid-inducible gene-I (RIG-I) pathway using polyinosinic:polycytidylic acid (poly(I:C)-LMW/LyoVec) and the TLR4 pathway. In blood collected ≤72 hours of ICU admission, interferon (IFN)α and TNFα were measured in unstimulated controls and after 24-hour poly(I:C) and 4-hour LPS stimulation, respectively. Poly(I:C) stimulation resulted in three response types. “Suppressed” patients had low control IFNα levels which remained low after stimulation, whereas “Peaked” patients produced high control IFNα with no increase after stimulation. “Responders” had at least double the amount of IFNα after stimulation over their control sample. RIG-I Suppressed children had higher organ dysfunction and fewer days alive and off mechanical ventilation. TLR4 suppression (TNFα≤200pg/ml) was again associated with worse outcomes and 60% were also RIG-I suppressed. The 33 patients with early suppression in both RIG-I and TLR4 pathways (compared to 70 others) had higher proinflammatory serum cytokines (IL-8, TNFα), more prolonged (≥7 days) multiple organ dysfunction (30.3% vs 8.6%, p=0.004), and prolonged hypoxic respiratory failure (39.4% vs 11.4%, p=0.001). Identification of RIG-I/TLR4 pathway suppression during severe influenza infection may provide an opportunity to modulate the immune response and improve outcomes.