Sepsis, a clinical syndrome occurring in patients following infection or injury, is a leading cause of morbidity and mortality worldwide. CD86 (B7-2) is a costimulatory molecule on antigen-presenting cells and plays critical roles in immune responses. In the current study, we investigated the association of two CD86 polymorphisms, rs1129055G/A and rs17281995G/C, with susceptibility to pneumonia-induced sepsis and examined the effects of these two polymorphisms on gene expression in monocytes. CD86 rs1129055G/A and rs17281995G/C were identified in 192 pneumonia-induced septic patients and 201 healthy controls. Data showed that frequencies of the rs1129055GA and AA genotypes were significantly lower in patients than in controls (odds ratio [OR]=0.57, 95 % confidence interval [CI], 0.35-0.93, p=0.023, and OR=0.40, 95 % CI, 0.23-0.71, p=0.002). Interestingly, the other polymorphism, rs17281995G/C, revealed significantly increased numbers in pneumonia-induced sepsis compared to controls (OR=1.85, 95 % CI, 1.07-3.20, p=0.025). Further analyses about CD86 gene expression revealed that both messenger RNA (mRNA) and protein levels of CD86 were downregulated in monocytes from controls carrying rs17281995GC genotype than those carrying wild-type rs17281995GG genotype (p=0.022 and p=0013). These results suggest that polymorphisms in CD86 gene have diverse effects on the pathogenesis of pneumonia-induced sepsis, in which rs17281995G/C may increase the risk of the disease by interfering gene expression of CD86 in monocytes.