Currently, there is no vaccine available against Chagas' disease. Immune abnormalities induced by T. cruzi pose particular difficulties for vaccine development, since immunological memory must be able to overcome them to prevent spread of infection/sequelae. We have previously demonstrated that experimental vaccination with live CL-14 trypomastigotes does not induce polyclonal lymphocyte activation, immunosuppression, or pathology and efficiently immunizes against virulent T. cruzi. Herein we show that: (1) expansion of CD4+ and CD8+ subsets peaks 2 weeks after infective challenge in both challenged-vaccinated mice and infected controls, but the former exhibit a smaller increase in blastogenesis and in the numbers of activated CD11a(hi)CD4+ and CD11a(hi)CD8+ cells; (2) in long-term-vaccinated mice, expansion of activated subsets (CD62Llo/- and CD11a(hi)) is accelerated among CD8+ PBL 1 week after challenge; (3) challenged-vaccinated mice retract the CD8+-activated subset 5 weeks after challenge, different from infected controls; (4) protection conferred by CL-14 immunization can be adoptively transferred to naïve recipients with lymphocyte suspensions, and prior depletion of CD8+ (but not of CD4+) cells abolishes protective immunity. Our findings indicate that protective immunity generated by CL-14 immunization involves a transient CD8+ recall response and is capable of preventing the signs of polyclonal lymphocyte activation induced by virulent challenge.