Abstract Aim To determine whether the use of antipyretic medications in the treatment of Streptococcus pneumoniae infection affects mortality in humans or animal models. Design A systematic search of Medline, Embase, and The Cochrane Register of Controlled Trials was undertaken to identify in vivo animal experiments or randomised, controlled trials in humans of antipyretic medication in S pneumoniae infection which reported mortality data. Meta-analysis was by inverse variance weighted method for odds ratios. Setting Antipyretics are recommended for the symptomatic treatment of various diseases caused by S pneumoniae. However, there is evidence that fever is a protective physiological response to infection, that treating fever secondary to infection may be harmful, and that some strains of S pneumoniae are temperature sensitive. Main outcome measures Mortality associated with antipyretic use in S pneumoniae infection. Results Four studies from two publications met the inclusion criteria and investigated the use of aspirin in animal models. The pooled estimate of mortality was an OR with aspirin treatment of 1.97 (95% CI 1.22 to 3.19). There were no suitable human studies identified. Conclusions A twofold increased risk of mortality was found with aspirin treatment in animal models of S pneumoniae infection. No relevant human studies were identified. It is difficult to generalise from animal models to clinical medicine, but based on these findings and the prevalence and severity of S pneumoniae infections worldwide, future study of the effects of antipyretic therapy in S pneumoniae infection in humans is recommended.