Objectives The Northern California Kaiser-Permanente Neonatal Sepsis Risk Calculator (SRC) has proved to be safe and effective in reducing laboratory tests, hospital admissions, and administration of antibiotics to patients at risk of early-onset neonatal sepsis (EONS). Many studies have focused on maternal chorioamnionitis as the principal risk factor for EONS. We wanted to know if the use of the SRC could be equally efficient in the context of several other infectious risk factors (IRF), in addition to chorioamnionitis, such as intrapartum maternal fever, GBS colonization and/or prolonged rupture of membranes (PROM). Methods Systematic study of neonates with ≥35 weeks gestational age (GA), born in our tertiary university hospital during a period of 18 months. Patients were retrospectively assessed with the SRC and its recommendations were compared with the actual management. A bivariate analysis of perinatal interventions, and outcomes was performed. Results A total of 5,885 newborns were born during the study period and 1783 mothers (31%) had at least one IRF. The incidence of culture-proven EONS was 0.5‰. The use of the SRC would have reduced laboratory evaluations (CBC and CRP) from 56.2 to 23.3%, and blood cultures, hospital admissions and antibiotic therapy from 22.9 to 15.5%, 17.8 and 7.6%, respectively. The management based on patients’ symptoms would have shown a reduction to 7.5% in all the outcomes of interest. Conclusions Both, the SRC and the management based on clinical findings, are safe and efficient to reduce the number of analytical studies, hospital admissions and administration of antibiotics to neonates with IRF.