Recent reports have indicated that IL-1[beta] is excessively released into the circulation during sepsis, and the expression level is closely correlated with the clinical course. Polymorphisms in the promoter region of IL-1B have been shown to affect LPS-induced IL-1[beta] transcription in vitro and IL-1[beta] plasma levels in healthy adults and to confer susceptibility to inflammatory diseases. However, it is not clear whether they confer susceptibility to sepsis after major trauma. The aim of this study was to search for association of polymorphisms (-1470G/C, -511T/C, and -31C/T) in the IL-1B gene promoter with the susceptibility to sepsis in a cohort of 238 major trauma patients. Genotyping of each patient for the three single-nucleotide polymorphisms was performed by restriction fragment length polymorphism-polymerase chain reaction method. Multivariate logistic regression analysis showed that the -1470 and -31 polymorphisms were associated with IL-1[beta] production by peripheral leukocytes in response to ex vivo LPS stimulation in an allele dose-dependent manner. Moreover, trauma patients carrying the -1470G or -31T alleles were more likely to develop sepsis compared with those with the -1470C or -31C allele (P = 0.014 and P = 0.038, respectively). Of the eight possible haplotypes composed of the three loci, the GCT and CTC haplotypes were associated with significantly higher and lower IL-1[beta] secretion (P = 0.005 and P = 0.035, respectively). Moreover, the GCT haplotype imparted higher risk of sepsis after severe injury (P = 0.04; odds ratio, 1.131; 95% confidence interval, 1.013-1.678). GCT homozygote patients also showed higher multiple organ dysfunction scores than CTC homozygote patients (P = 0.048). These data suggest that the IL-1[beta] promoter polymorphisms -1470G/C, -511T/C, and -31C/T may be functional both in vitro and in vivo. It may be possible to use these polymorphisms as relevant risk estimates for sepsis in trauma patients.