The objective of this study was to prospectively evaluate the incidence of neonatal sepsis after prolonged premature rupture of membranes (PROM), to correlate sepsis with gestational age and with the duration of PROM, and to evaluate the necessity for prophylactic antibiotic therapy in neonates born after PROM. Of 12,182 infants, 135 (1.1%) were delivered after PROM with a latency period of > 24 hours. Neonatal sepsis occurred in 11 infants (8.1%), 10 of whom were premature. The only term, septic newborn was a small-for-gestational-age infant. A latency period > 72 hours was not associated with an increased incidence of sepsis. Maternal fever, neonatal signs of infection including leukopenia, leukocytosis, thrombocytopenia, and positive gastric aspirate cultures, were not good predictors of sepsis. Of premature infants with PROM, 15% had sepsis, and thus the administration of prophylactic antibiotic therapy in these cases may be warranted. However, it may be unnecessary to administer prophylactic antibiotics to term, appropriate-for-gestational-age infants born after PROM.