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There is a general lack of effective and non-toxic chemotherapeutic agents for treating Chagas' disease. In the present work, we evaluated the in vitro activity of the calpain inhibitor MDL28170 against Trypanosoma cruzi relevant clinical forms.The effect of MDL28170 on bloodstream trypomastigotes at different concentrations was assessed by counting the parasites in a Neubauer chamber, which allowed the determination of IC50 values. Subsequently, parasite–macrophage interaction was assessed by two approaches: (i) peritoneal mouse macrophages were pre-infected with trypomastigotes for 3 h and then treated daily for 72 h with MDL28170; or (ii) bloodstream trypomastigotes were pre-treated with the calpain inhibitor for 1 h and then subjected to the infection assay.MDL28170 was capable of significantly reducing the viability of bloodstream trypomastigotes, presenting an IC50/24 h value of 20.4 µM. Also, parasites pre-treated with the inhibitor, at subinhibitory drug concentrations, prior to macrophage infection presented a clear dose-dependent inhibition profile, where the inhibition increased from 20% to 50% (in relation to control) as MDL28170 concentration rose from 6.25 to 50 µM. In addition, macrophages experimentally infected with T. cruzi that were treated with the calpain inhibitor presented a significant reduction in the percentage of infection even at the lowest concentrations (6.25 µM).These data may contribute to the study of the calpains in T. cruzi infection and add new in vitro insights into the possibility of exploiting calpains as promising targets to treat Chagas' disease.