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BACKGROUND: Neonatal sepsis is a health problem because it causes serious morbidity and mortality in neonate intensive care units. The susceptibility of neonates occurs due to the immaturity of immune system development as well as due to maternal and environmental risk factors that can cause infection. Identification of genetic variation in genes involved in the inflammatory process can help clarify the pathophysiology of sepsis in high-risk patients, useful for the development of new diagnostic tools, and specific management plans for more accurate predictions of patient’s prognosis. AIM: This study aims to determine the association between gene polymorphism of BPI rs4358188, CD14 rs2569190, IL1β rs1143643 or MMP16 rs2664349 and the incidence of neonatal sepsis. METHODS: Cross-sectional observational studies with genomic DNA samples from infants with sepsis and non-sepsis which were stored according to the standard storage of genetic materials in the Biomedical Laboratory of Faculty of Medicine Universitas Andalas Padang City, Indonesia. This study is part of a previous study by Rukmono P. Continued with PCR examination, sequencing and bioinformatics analysis. RESULTS: Only IL1β rs1143643 G > A gene polymorphism was associated with the incidence of neonatal sepsis and was statistically significant (p = 0.017). No significant association was found between gene polymorphisms of BPI rs4358188 G > T, CD14 rs2569190 A>G or MMP16 rs2664349 G > A and neonatal sepsis (p > 0.05). CONCLUSION: Gene polymorphism of IL1β rs1143643 G > A is associated with the incidence of neonatal sepsis.