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Objective To assess whether procalcitonin-guided decision making can safely reduce the duration of antibiotic treatment in neonatal late onset sepsis.Design Prospective multicentre, randomised open label trial.Setting 33 level 3 and level 2B neonatology departments in France.Participants Newborn babies born after 24 weeks’ gestation, of postconceptional age 24-45 weeks and after 4 days of life, weighing more than 700 g, with suspected or proven late onset sepsis, requiring antibiotics for more than 48 hours, and without meningitis, septic shock, and deep-seated infection.Interventions Participants were randomly assigned to procalcitonin-guided or usual care antibiotic treatment. In the procalcitonin-guided group, procalcitonin concentration was measured at randomisation and then every two days. A non-binding recommendation to discontinue antibiotics was given if the procalcitonin concentration was 0.5 µg/L or lower. In the usual care group, treatment was provided according to local protocols.Main outcome measures The primary outcome was the duration of antibiotic treatment (under the superiority hypothesis). The key secondary outcome was non-inferiority for mortality (margin 3%) at day 28 after randomisation.Results Between February 2019 and February 2023, 248 newborns were randomised to the procalcitonin-guided group and 256 to the usual care group. In the intention-to-treat analysis, the median duration of antibiotic treatment was eight days (interquartile range (IQR) 5.0-12.0) in the procalcitonin-guided group versus 10 days (8.0-13.0) in the usual care group (absolute difference between groups −2.0 (IQR −3.8 to −1.0), P<0.001). At day 28, the proportion of death was six of 248 newborns (2.4%) in the procalcitonin-guided group versus 10 of 256 (3.9%) in the usual care group (absolute difference between groups −1.5% (95% confidence interval (CI) −5.0 to 1.8). The proportion of recurrence was seven of 248 (2.8%) newborns in the procalcitonin-guided group versus 10 (3.9%) of 256 in the usual care group (absolute difference between groups −1.1% (95% CI −4.6 to 2.3).Conclusion In this study population, the use of procalcitonin significantly reduced the duration of antibiotic treatment in neonatal late onset sepsis, without increasing mortality or serious adverse events.Trial registration NCT03730636.