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ObjectiveAssess the impact of introducing a consensus guideline incorporating an adapted Sepsis Risk Calculator (SRC) algorithm, in the management of early onset neonatal sepsis (EONS), on antibiotic usage and patient safety.DesignMulticentre prospective studySettingTen perinatal hospitals in Wales, UK.PatientsAll live births ≥34 weeks’ gestation over a 12-month period (April 2019–March 2020) compared with infants in the preceding 15-month period (January 2018–March 2019) as a baseline.MethodsThe consensus guideline was introduced in clinical practice on 1 April 2019. It incorporated a modified SRC algorithm, enhanced in-hospital surveillance, ongoing quality assurance, standardised staff training and parent education. The main outcome measure was antibiotic usage/1000 live births, balancing this with analysis of harm from delayed diagnosis and treatment, disease severity and readmissions from true sepsis. Outcome measures were analysed using statistical process control charts.Main outcome measuresProportion of antibiotic use in infants ≥34 weeks’ gestation.Results4304 (14.3%) of the 30 105 live-born infants received antibiotics in the baseline period compared with 1917 (7.7%) of 24 749 infants in the intervention period (45.5% mean reduction). All 19 infants with culture-positive sepsis in the postimplementation phase were identified and treated appropriately. There were no increases in sepsis-related neonatal unit admissions, disease morbidity and late readmissions.ConclusionsThis multicentre study provides evidence that a judicious adaptation of the SRC incorporating enhanced surveillance can be safely introduced in the National Health Service and is effective in reducing antibiotic use for EONS without increasing morbidity and mortality.