Tumor necrosis factor-alpha (TNF-alpha) plays a central role in the pathophysiology of sepsis. Levels of TNF-alpha are directly correlated with severity in meningococcal disease (MD). A polymorphism in the promoter region of the TNF-alpha gene is associated with differences in the secretion of TNF-alpha. The TNF2 allele is associated with higher constitutive and inducible levels of TNF-alpha secretion than is the TNF1 allele. To investigate whether possession of the TNF2 allele is associated with severity in MD, the frequency of TNF1 and TNF2 alleles in 98 children with MD was compared. There were more deaths among children who had the TNF2 allele (P = .03; relative risk [RR], 2.5; 95% confidence interval [CI], 1.1-5.7) than in those who did not. There was also an increased risk of severe disease in children with the TNF2 allele (P = .02; RR, 1.6; 95% CI, 1.1-2.3). Possession of the TNF2 allele predisposes to a worse outcome in children with meningococcal infection.