We investigated the protective effect of Trypanosoma rangeli against infection with Trypanosoma cruzi in animal models of various ages and with different doses of inoculum. The age of the mice and the dose of parasites determined the course of the infection. When T. cruzi was inoculated into mice after challenge with T. rangeli, parasitaemia was more controlled, mortality decreased and histopathology showed lower inflammatory infiltration and pseudocysts. This study proposes a new murine model of the protective effect of recombinant proteins of T. rangeli for possible application in the vaccines field.