Chronic Chagas' disease cardiomyopathy (CCC) is the most important clinical outcome of infection by the parasite Trypanosoma cruzi, affecting 18 million individuals in Latin America. One-third of CCC patients develop heart failure due to end-stage dilated cardiomyopathy, and their survival is reduced by 50% compared to patients with other cardiomyopathies. Genetic susceptibility may play a role in the differential survival of severe CCC patients. Given the role of TNF-alpha in the progression of heart failure, and the increased TNF-alpha plasma and heart tissue levels observed in these patients, we chose TNF as a candidate gene for increased mortality in severe CCC patients. We typed the TNFa microsatellite and the -308 TNF promoter polymorphism and then analyzed the survival curves of 42 patients with severe ventricular dysfunction (left ventricular ejection fraction<or=40%) according to the presence of the TNF2 promoter allele or the TNFa2 microsatellite allele, both previously associated with high TNF-alpha production. Multivariate regression analysis (Cox proportional hazards model) revealed the TNF genotype and age of onset of severe CCC as independent predictors of mortality in severe CCC. We showed that patients positive for TNF2 or TNFa2 alleles display a significantly shorter survival time compared to those carrying other alleles; the median survival times were 2.9 and 8 months, respectively (HR(adj)=2.28, p=0.020). We have identified for the first time a genetic factor related to reduced survival in severe Chagas' disease cardiomyopathy. The association of TNF genotype with earlier death in CCC should be taken into account when planning therapeutic intervention.