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A maternal diagnosis of chorioamnionitis, based on maternal peripartum fever of 100.4°F alone, is commonly used as an indication for blood work and antibiotic treatment in newborns. New strategies such as the Kaiser Permanente early-onset sepsis (EOS) calculator have proven effective in identifying high-risk newborns and reducing unnecessary antibiotic administration.Retrospective data from October 2017 to September 2018 from 297 well-appearing newborns ≥35 weeks' gestational age (GA) with maternal chorioamnionitis showed that 93.6% had blood work and 90.2% were treated with antibiotics. This was despite no culture-positive cases of sepsis. Our aim was to reduce by 50% blood work evaluation and antibiotic treatment within a 6-month period.Using plan-do-study-act (PDSA) cycles, we adopted the Kaiser Permanente EOS calculator. We collected longitudinal data to track the outcomes after its implementation.In 423 newborns with maternal chorioamnionitis triaged with the EOS calculator from October 2018 to July 2020, the rates of blood culture and antibiotic treatment decreased from 93.6% to 26.7% and 90.2% to 12.3% (P.0001). In the larger population of 6426 newborns ≥35 weeks' GA, the rate of blood culture and antibiotic treatment decreased from 12.8% to 5.8% and 9.9% to 2.5% (P.0001).The EOS calculator substantially and safely decreases blood work and antibiotic administration in asymptomatic newborns with maternal chorioamnionitis.Our findings provide further evidence for the effectiveness and safety of the EOS calculator.Video abstract available athttps://journals.lww.com/advancesinneonatalcare/Pages/videogallery.aspx.