Potential limitations of this study should be addressed. First, although we knew that different pathogens had different impact on severity and outcomes of sepsis, we did not perform stratification analysis by different pathogens due to small number of cases with a definite microbiologic diagnosis. Second, we did not resequence these genes or select tag SNPs for genotyping. Instead, only ten potentially functional SNPs in TNF, LTA, TNFRSF1A and TNFRSF1B were included in our study, which was far from comprehensive. Indeed, these four genes are highly polymorphic. Therefore, it was possible that some important SNPs might be missed or the observed association might be due to other polymorphisms in LD with the studied ones. Additionally, assuming the prevalence of 0.01 for severe sepsis and using a significance level of 0.05, our study with 432 severe sepsis patients and 624 healthy controls had about 80% power to detect a 5% risk allele with an odds ratio of 1.63. Variant with an effect size smaller than this cannot convincingly be excluded based on these results. Therefore, our results cannot exclude variant associations with weaker effects between severe sepsis and the other three candidate genes (LTA, TNFRSF1A, TNFRSF1B). A more highly powered study involving thousands of subjects may yet exclude the role of these variants in severe sepsis susceptibility and outcomes.