BACKGROUND: Leptospirosis is a zoonotic bacterial infection occurring worldwide. It is of particular public health concern due to its global distribution, epidemic potential and high mortality without appropriate treatment. The method for the management of leptospirosis, particularly in severe disease, is clouded by methodological inconsistency and a lack of standardized outcome measures. The study this protocol details aims to develop a core outcome set (COS) for leptospirosis research. A COS is a set of outcomes with international consensus as a minimum for reporting in future studies focusing on leptospirosis. Establishing a COS will contribute to harmonizing Leptospirosis treatment research and will be instrumental in constructing a high-quality evidence base to feed into a planned future rigorous international clinical trial on leptospirosis. METHODS: The COS-LEP study will employ a COS development methodology standardized by the COMET initiative framework. This includes (1) a systematic review of available quantitative and qualitative literature reporting therapeutic response and safety outcomes and measures; (2) focused interviews with healthcare professional and people treated for leptospirosis exploring outcomes of interests using qualitative methodology; (3) narrowing the choice of outcomes by international consensus using a Delphi survey process; and (4) undertaking a hybrid consensus meeting with key stakeholders to build the final COS. DISCUSSION: This protocol describes the method to develop the first core outcome set for use in human leptospirosis studies. This will not only be a key feature in the design of a future definitive randomized controlled trial, but also provide a structure for clinicians and researchers collecting treatment cohort data in the various settings where leptospirosis is a public health issue.