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Introduction Fever commonly leads to healthcare seeking and hospital admission in sub-Saharan Africa and Asia. There is only limited guidance for clinicians managing non-malarial fevers, which often results in inappropriate treatment for patients. Furthermore, there is little evidence for estimates of disease burden, or to guide empirical therapy, control measures, resource allocation, prioritisation of clinical diagnostics or antimicrobial stewardship. The Febrile Illness Evaluation in a Broad Range of Endemicities (FIEBRE) study seeks to address these information gaps.Methods and analysis FIEBRE investigates febrile illness in paediatric and adult outpatients and inpatients using standardised clinical, laboratory and social science protocols over a minimum 12-month period at five sites in sub-Saharan Africa and Southeastern and Southern Asia. Patients presenting with fever are enrolled and provide clinical data, pharyngeal swabs and a venous blood sample; selected participants also provide a urine sample. Laboratory assessments target infections that are treatable and/or preventable. Selected point-of-care tests, as well as blood and urine cultures and antimicrobial susceptibility testing, are performed on site. On day 28, patients provide a second venous blood sample for serology and information on clinical outcome. Further diagnostic assays are performed at international reference laboratories. Blood and pharyngeal samples from matched community controls enable calculation of AFs, and surveys of treatment seeking allow estimation of the incidence of common infections. Additional assays detect markers that may differentiate bacterial from non-bacterial causes of illness and/or prognosticate illness severity. Social science research on antimicrobial use will inform future recommendations for fever case management. Residual samples from participants are stored for future use.Ethics and dissemination Ethics approval was obtained from all relevant institutional and national committees; written informed consent is obtained from all participants or parents/guardians. Final results will be shared with participating communities, and in open-access journals and other scientific fora. Study documents are available online (https://doi.org/10.17037/PUBS.04652739).