The health burden of Chagas' disease (resulting from Trypanosoma cruzi infection) in Latin America (estimated to outweigh that of malaria by 5-fold and affect 2-6 million people in Mexico alone) has motivated development of therapeutic vaccines to prevent infection progression to severe disease. Our economic model for a Chagas' therapeutic vaccine in Mexico suggests that a vaccine would be highly cost-effective and in many cases economically dominant (providing both cost savings and health benefits) throughout a range of protection durations, severe adverse event risk, and dosing regimens and would be most likely to provide a positive return on investment if the vaccine prevented (rather than delayed) the onset of cardiomyopathy.