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HLA\u2010G and its murine functional homolog Qa2 have well\u2010recognized immunomodulatory properties. We evaluated the <jats:italic>HLA-G<\/jats:italic> 3\u2032 untranslated region (3\u2032UTR) polymorphic sites (associated with mRNA stability and target for microRNA binding) and HLA\u2010G tissue expression (heart, colon, and esophagus) in patients presenting Chagas disease, stratified according to the major clinical variants. Further, we investigated the transcriptional levels of Qa2 and other pro\u2010 and anti\u2010inflammatory genes in affected mouse tissues during <jats:italic>T. cruzi<\/jats:italic> experimental acute and early chronic infection induced by the CL strain. Chagas disease patients exhibited differential <jats:italic>HLA-G<\/jats:italic> 3\u2032UTR susceptibility allele\/genotype\/haplotype patterns, according to the major clinical variant (digestive\/cardiac\/mixed\/indeterminate). 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