The JG strain is the least virulent while the CL-Brener clone is one of the most virulent Trypanosoma cruzi populations in young rats. In this study, we determined that the parasitemia peak values in CL-Brener clone-infected adult rats were 50-fold lower than in young rats and that mortality was null as compared to 45% death in young rats. Low parasitemia, milder and sustained myocarditis and myositis characterized JG infections. CL-Brener clone caused a significantly higher production of pro-inflammatory cytokines and higher expansion of CD3 + CD4 − CD8 − , double-negative (DN) T cells, during the acute phase in both adult and young rats. DN T cell frequencies correlated with IFN-γ levels. These findings may explain the higher inflammation and fast acute phase resolution in CL-Brener infection. In young rats, IL-10 levels were similar in both infections. The IL-10/IFN-γ ratio was higher in JG acute infection in accordance with the milder inflammation and parasite persistence leading to a chronic phase. In conclusion, virulence and pathogenicity depend on T. cruzi ability to induce expansion of DN T cells and production of specific cytokines.