Host genetic factors are thought to contribute to susceptibility and outcome in infectious diseases. A polymorphism in a proinflammatory gene, tumor necrosis factor-alpha (TNFA - 308), was recently found to be associated with susceptibility to typhoid fever. As the observation was made in hospitalized patients, a potential confounder could be that the TNFA polymorphism is associated with the severity of established illness resulting in hospital admission rather than susceptibility to disease. We tested whether the association with TNFA - 308 is present also in typhoid fever patients enrolled in a community-based case-control study in an endemic area in Indonesia. Common polymorphisms in other proinflammatory genes were assayed as well. Samples of patients with blood culture-confirmed typhoid fever (n = 90) and paratyphoid fever (n = 26) and fever controls (n = 337) were compared with those of community controls (n = 322). In these groups, we analyzed polymorphisms in TNFA by PCR and RFLP, polymorphisms of IFNG, IL1A, IL1B, IL1R1, TNFRSF1A, CASP1, and CRP by Sequenom MassArray (San Diego, CA), and polymorphisms in IL12B and IFNGR1 by fragment length analysis. The IL1R1 polymorphisms were nearly absent in the Indonesian population. The TNFA - 308 polymorphism was not associated with typhoid fever (OR 0.35, 95% CI 0.1-1.0) in this population. The polymorphisms at TNFA - 238 or in IFNG, IL1A, IL1B, IL12B, TNFRSF1A, IFNGR1, CASP1, and CRP were also not associated with typhoid or paratyphoid fever. We conclude that polymorphisms in proinflammatory genes do not contribute to susceptibility to typhoid fever and, in view of earlier findings, suggest that the TNFA - 308 polymorphism is likely related to severity of established disease rather than to susceptibility per se.