To evaluate the tumor necrosis factor (TNF) a-e microsatellite polymorphism in Chagasic patients, we studied 162 patients stratified according to the major clinical variants (cardiac, digestive, digestive plus cardiac, and indeterminate forms) and 221 healthy controls. TNF microsatellite alleles were typed using genomic DNA amplified with specific primers. Statistical analyses were performed using the GENEPOP and ARLEQUIN softwares and the two-tailed Fisher exact test. The TNFa2, TNFa7, TNFa8, TNFb2, TNFb4, TNFd5, TNFd7, and TNFe2 alleles were overrepresented, whereas the TNFb7 and TNFd3 alleles were underrepresented when clinical variants of Chagas' disease or the patient group as a whole were compared with controls. Twelve TNF haplotypes were associated with susceptibility to or protection against Chagas' disease, considered as a whole or stratified into clinical variants. Many of these haplotypes encompassed the above-described susceptibility/protective alleles. These results indicate that the TNF chromosomal region is relevant for Chagas' disease development.