Neonatal SOFA score was reported as an accurate predictor of mortality while the prognostic accuracy of SIRS criteria is unknown. The aim was to compare neonatal SOFA and SIRS criteria for the prediction of late onset sepsis-related mortality in preterm newborns. Newborns ≤ 32 weeks with late onset sepsis were retrospectively studied. Neonatal SOFA and SIRS criteria were calculated at onset of sepsis (T0), and after 6 ± 1 (T1), 12 ± 3 (T2) and 24 ± 3 h (T3). Outcome was death during antibiotic treatment for late onset sepsis. We studied 112 newborns with gestational age 26.9 ± 2.3 weeks; 11% met the study outcome. Neonatal SOFA was significantly higher in non-survivors vs. survivors at all time intervals; SIRS criteria were significantly higher in non-survivors vs. survivors at T1, T2 and T3. Neonatal SOFA increased over time in non-survivors (p = 0.003). At T0, the area under receiver operating characteristics curve was significantly higher for neonatal SOFA score than SIRS criteria (0.950 vs. 0.569; p = 0.0002), and the best calculated cut-off for T0 neonatal SOFA score was 4. In multivariate analysis T0 and T1 neonatal SOFA were predictors of late onset sepsis-related mortality (p = 0.048 and p < 0.001).  Conclusion: Neonatal SOFA score showed greater discriminatory capacity for mortality than SIRS criteria and might be helpful to plan management for patients at higher risk of death. What is Known: • Neonatal SOFA score may be an accurate prognostic tool. • No prognostic score has been fully standardized for septic newborns in NICU. What is New: • Neonatal SOFA score outperformed SIRS criteria for the prediction of prognosis in preterm infants with late onset sepsis. • Neonatal SOFA score assessed at onset of sepsis and 6 hrs later is a predictor of mortality.