Abstract Influenza virus infects 5–20% of the population annually, leading to considerable morbidity and mortality especially in children. Robust biomarkers, reflecting the host immune response, are needed to identify patients at risk of prolonged illness or death. Eicosanoids, a family of bioactive arachidonic acid metabolites produced by the host in response to influenza infection, have pro- and anti-inflammatory properties. This study aimed to assess the relationship between the host lipid response at ICU admission with clinical outcomes in a multicenter cohort of 105 children with influenza-related illness (PICFLU study). We developed a mass spectrometry-based method to quantify >100 lipid metabolites from nasopharyngeal swabs and endotracheal aspirates. The bioactive lipid profile in influenza infected children was impacted by multiple factors including patient age and bacterial coinfection. Patients coinfected with methicillin-resistant Staphylococcus aureus and influenza had significantly elevated levels of pro-inflammatory lipids and concomitantly lower levels of anti-inflammatory 15-lipoxygenase metabolites. Interestingly, children that presented with high levels of lipids including prostaglandin E2 and 12-hydroxyeicosatetraenoic acid were more likely to have fatal outcomes despite reports indicating these lipids have opposing immunomodulatory activity. These results suggest children at risk of mortality have an amplified bioactive lipid immune response that may negatively impact disease resolution. Our study provides evidence that bioactive lipids are potential prognostic biomarkers of patient immune response phenotype, and may help to identify children at risk of influenza-related death.