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Abstract Background Sepsis is a clinical syndrome that is frequently observed after injury or infection, representing a leading cause of mortality worldwide. CD86 (B7-2) is a co-stimulatory molecule on antigen-presenting cells, and plays critical roles in immune responses. Methods A total of 135 sepsis patients and 151 healthy controls were recruited in the current case-control study. Hardy-Weinberg equilibrium (HWE) conformity was examined to assess the representativeness of the study population. CD86 gene polymorphisms were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The relative expression of CD86 mRNA was estimated via quantitative real-time PCR (qRT-PCR). Chi-square test was performed to estimate the associations between CD86 gene polymorphisms and sepsis risk, and the results were presented through odds ratio (OR) and 95% confidence intervals (CI). Results The genotype distributions of CD86 polymorphisms in the case and control groups conformed to HWE. The GA genotype of the polymorphism rs1129055 was significantly correlated with an increased risk of sepsis (OR = 2.540, 95%CI = 1.288–5.008). The TT genotype of rs1915087 was a risk factor for sepsis (OR = 2.769, 95%CI = 1.292–5.935). High linkage disequilibrium was observed between the two polymorphisms (D′ = 1.0, r2 = 0.955). However, no significant association was observed between CD86 polymorphisms and its gene expressions (P > 0.05 for all). Conclusion CD86 gene polymorphisms rs1129055 and rs1915087 may increase the risk of sepsis. [ABSTRACT FROM AUTHOR]