BACKGROUND: Olfactomedin 4 (OLFM4) gene polymorphisms have been associated with variations in inflammatory responses and the severity of infections. This study aimed to investigate the association between OLFM4 single nucleotide polymorphisms (SNPs) rs17552047 and rs1891944 and severe outcomes in preterm neonatal sepsis. METHODS: A prospective observational cohort study was conducted from April 2023 to April 2024, involving all preterm infants diagnosed with neonatal sepsis. Genotyping was performed using real-time polymerase chain reaction, and the associations with severe outcomes were analyzed using genetic models (dominant, recessive, and additive) through multivariate logistic regression and survival analysis. RESULTS: Among the 174 preterm newborns included in the study, 39 experienced severe outcomes. The AA/AG genotypes of SNP rs17552047 and TT/TC genotypes of rs1891944 were associated with a reduced risk of severe outcomes (adjusted hazard ratio: 0.271, 95 % confidence interval [CI]: 0.115-0.641, p = 0.003, and adjusted hazard ratio: 0.349, 95 % CI: 0.175-0.698, p = 0.003, respectively). The odds of severe outcomes decreased by 65 % for each additional A allele (95 % CI: 0.15-0.78, p = 0.01). The model incorporating both SNPs and clinical variables demonstrated good predictive capability (area under the receiver operating characteristic curve: 0.826, 95 % CI: 0.748-0.903, p = 0.03). CONCLUSIONS: The OLFM4 rs17552047 AA/AG and rs1891944 TT/TC genotypes have been linked to favorable outcomes in neonatal sepsis. These SNPs hold promise for predicting severe outcomes in neonatal sepsis.