Summary Objective To determine whether antipyretic treatment for influenza infection influences the risk of mortality in animal models and humans. Design A systematic search of Medline, Embase and the Cochrane Register of Controlled Trials was undertaken to identify randomized placebo-controlled trials of antipyretic use in influenza infection in animal models or humans that reported mortality. A quantitative meta-analysis of the risk of death using Peto's one step odds ratio with calculation of the pooled risk of death and standard evaluation of heterogeneity was undertaken. Setting Not applicable. Participants Not applicable. Main outcome measures Risk of mortality associated with antipyretic use in influenza infection. Results Eight studies from three publications met the inclusion criteria. No human studies were identified. The risk of mortality was increased by antipyretic use in influenza-infected animals with a fixed effects pooled odds ratio of 1.34 (95% CI 1.04–1.73). An increased risk was observed with aspirin, paracetamol and diclofenac. Conclusion In animal models, treatment with antipyretics for influenza infection increases the risk of mortality. There are no randomized placebo-controlled trials of antipyretic use in influenza infection in humans that reported data on mortality and a paucity of clinical data by which to assess their efficacy. We suggest that randomized placebo-controlled trials of antipyretic use in human influenza infection are urgently required, and that these are sufficiently powered to investigate a potential effect on mortality.