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Introduction: Worldwide, neonatal mortality remains high accounting for 47% of childhood deaths in 2019 and including an estimated 500 000 deaths from neonatal infections. While 42% of global neonatal deaths occur in sub-Saharan Africa, there is limited understanding of population-level burden and aetiology of neonatal infections outside tertiary-level institutions., Methods and Analysis: We aim to implement the first population-level surveillance for bloodstream infections and meningitis among neonates aged <28 days in South Africa. Tier 1 will include national surveillance of culture-confirmed neonatal infections at all public-sector hospitals describing infection incidence risk, pathogen profile and antimicrobial susceptibility by institution, province and healthcare level (2014-2021). Tier 2 (nested within tier 1) will be conducted at six regional neonatal units over 12 months, will compare the clinical characteristics of neonates with early-onset and late-onset infections and identify potentially modifiable risk factors for mortality. Through tier 2, we will determine the antimicrobial susceptibility of neonatal pathogens, evaluate the appropriateness of empiric antibiotic prescribing and determine the genomic epidemiology of multidrug resistant bacterial and fungal pathogens., Ethics and Dissemination: Ethics clearance was obtained from the Human Research Ethics Committee of the University of the Witwatersrand (M190320). Funding for the study was obtained through a grant from the Bill and Melinda Gates Foundation (OPP1208882). Baby GERMS-SA aims to impact on national policy, resource allocation and neonatal guidelines by describing the national burden of neonatal infections in South Africa. In addition, end-users in neonatal units will benefit from a facility-level dashboard displaying key indicators of the surveillance findings., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)