Objective To study the association between interleukin-8 (IL-8) rs4073 polymorphisms and susceptibility to sepsis in full-term neonates through a prospective study. Methods A total of 50 neonates who were diagnosed with sepsis based on positive blood culture from January to December 2017 were enrolled as the sepsis group. Fifty neonates who had clinical symptoms and negative blood culture were enrolled as the clinical sepsis group. Fifty neonates without infection were enrolled as the control group. Sequencing was used to detect the polymorphisms of IL-8 rs4073. The three groups were compared in terms of the frequencies of genotypes and alleles. A multivariate logistic regression analysis was used to investigate the association of IL-8 rs4073 genotypes with sepsis in full-term neonates. Results There were significant differences in the frequencies of genotypes and alleles at IL-8 rs4073 among the three groups (P < 0.05). The logistic regression analysis showed that a low gestational age and TT genotype at IL-8 rs4073 were risk factors for the pathogenesis of sepsis in neonates (P < 0.05). Conclusions The full-term neonates with TT genotype at IL-8 rs4073 may be susceptible to sepsis.