Background: Empiric antibiotic treatment for term neonates with prolonged tachypnea after birth is an acceptable approach worldwide. Evidence is needed to minimize its use, especially among neonates with a low risk for infectious outcome and hereby prevent harmful effects. Objectives: To assess the rates of true infection among neonates with prolonged tachypnea and minimize the use of antibiotic treatment by identifying neonates with low risk for true infection. Methods: This is a retrospective cohort study conducted between November 2017 and December 2023. Demographic, clinical data, rates of infectious outcome and antibiotic treatment were collected. Outcomes were compared among neonates with prolonged tachypnea with and without perinatal risk factors for infection. Results: 587 neonates were included. The incidence of an infectious outcome among neonates with perinatal risk factors was significantly higher than among neonates without any risk factor (2.9% versus 0.5% respectively). Among neonates without perinatal risk factors for infection 99.3% had no infectious outcome, but antibiotic usage rates were high (76%). Conclusions: Rates of infection are low among infants with tachypnea after birth, especially when no perinatal risk factor for infection was present. We propose an algorithm to identify neonates who can be managed through clinical follow-up and prevent harmful antibiotic treatment.