Chagas disease is a public health problem in Latin America and its treatment is based on the use of benznidazole or nifurtimox compounds. Both present problems such as resistance, ineffi ciency in chronic infection and cytotoxic effects. New compounds such as posaconazole and amiodarone have been tested against T. cruzi and shown to be effective. In addition, new molecules have been synthesized and tested against T. cruzi. Because this protozoan is highly pathogenic, even with a number of cases of accidental laboratory infections, few laboratories located outside Latin America are authorized to work with its infective developmental stages. On the other hand, Trypanosoma dionisii is a non-pathogenic protozoan phylogenetically related to T. cruzi and that shares similar strategies to complete its life cycle in mammalian cells in vitro. Here, we describe a comparative analysis of the sensitivity of both parasites to benznidazole, posoconazole and amiodarone. We also analyzed the morphological effects of these compounds on both Trypanosoma species using electron microscopy. Our results show that T. dionisii is more sensitive to the compounds tested than T. cruzi. They also support a previous suggestion that it may constitute an excellent model for large scale screening of compounds against T. cruzi.