Abstract Association between the major histocompatibility complex (MHC) and the susceptibility/resistance to acquire Chagas' disease has been largely demonstrated. To study the role of candidate genes in this susceptibility/resistance to Chagas, we designed a population‐genetic‐based case‐control approach (chagasic n = 104 and controls n = 60) and tested the presence of genotype and linkage disequilibrium on microsatellite loci establishing specific landmarks for the MHC, interleukin (IL)‐2, IL‐2Rβ chain, IL‐4, IL‐10, and natural resistance‐associated mactophage protein 1 (NRAMP1). After demonstrating no genetic stratification among cases and controls ( F st were not different from 0), we found significant allelic differences among chagasic patients and controls at microsatellite locus D6S291 (MHC) and at the microsatellite pointing out the IL‐10. At the MHC, we found significant differences between patients and controls in Hardy–Weinberg equilibrium‐expected genotype proportions. Additionally, MHC II‐locus‐inferred haplotypes in chagasic patients exhibited strong significant departures from the expected proportions predicted by the second Mendelian law. The linkage disequilibrium pattern at MHC involves a region of approximately 10 cM. These results replicate previous analyses and suggest that presence of epistasis between MHC with humoral systems, such as IL‐10, could be underlying the susceptibility/resistance to Chagas' disease.