Abstract: BACKGROUND: Neonatal sepsis is a major cause of morbidity and mortality among neonates. Nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a core element for innate immune protection. The study aims to estimate the expression of NLRP3 inflammasome in full term newborn infants who suffer from late onset sepsis, in order to assess its diagnostic value. METHOD: This case-control study was conducted in NICU. 40 newborns with late onset sepsis, and 40 control neonates were included. The analysis of NLRP3 inflammasome was done by ELISA. RESULTS: There was a significant elevation of NLRP3 inflammasome in the serum of neonates with late onset sepsis group than the control group, P values were < 0.001, and the best cut off value of NLRP3 to detect late onset septic was > 3 ng/ml with sensitivity of 92.5% and specificity of 97.5%. Receiver operating characteristic curve showed that the best cut off point of NLRP3 to predict mortality in cases group was > 7.29 with sensitivity of 75.0%, specificity of 91.67%, PPV of 50.0%, NPV of 97.1% and total accuracy of 0.84%. n-SOFA scoring system increased significantly among LOS group and there was positive correlation with NLRP 3 inflammasome, P < 0.012. CONCLUSION: NLRP3 inflammasome can be used for the diagnosis of late onset neonatal sepsis. The increase of its values was not affected by gender, birth weight, gestational age and postnatal age. It was the novel sepsis markers that were not fully studied in neonatal population. The prognostic values may need further studies.