Background: Pathological coagulation system activation is linked to neonatal sepsis, which leads to disseminated intravascular coagulation. Late-onset sepsis (LOS) in preterm neonates leads to serious morbidities and increased mortality. Aim and objectives: The purpose of this research was to assess how pentoxifylline affectes protein C in septic preterm infants as well as their clinical development and outcomes. Patients and methods: Eighty preterm newborns who were hospitalized in Kasr Alaini, Cairo University Hospital's neonatal critical care units and with clinical or blood culture-proven LOS participated in this double-blinded, randomized controlled experiment. The pentoxifylline group got pentoxifylline (5 mg/kg/hour for six hours), whereas the control group received normal saline as a placebo. Both infusions were administrated for six successive days. Protein C levels were measured before and after the intervention. Result: Gram-negative sepsis was predominant with Klebsiella pneumonia being the most common isolated organism. After the intervention, there was a significant increase in protein C levels in the pentoxifylline group (P value = 0.020). Significant reductions in the duration of antimicrobial therapy,duration of hospital stay in survivors and continuous positive airway pressure therapy, (P values =0.001, 0.012 and 0.03 respectively) were documented, as well as the decreased requirement for plasma transfusions (P value = 0.03). Conclusion: In preterm newborns with LOS, pentoxifylline has a good impact on the protein C system and lengths of antibiotic treatment, hospital stay and continuous positive airway pressure therapy.