We studied the role of Trypanosoma cruzi reinfection in regard to inflammatory and cytokine response at the inoculation site, lymph node and heart. We reinfected Balb/c mice intradermically into the hind foot-pad with natural infective metacyclic trypomastigotes. They were followed from 24 h to 30 days after the last reinfection. At the inoculation site 24 h after the last re-infection, the infiltrating inflammatory cells increased dramatically with respect to baseline inflammation, reaching maximum infiltrates for the third day. In contrast, parasite DNA was undetectable 24 h after inoculation, despite poor cytokine induction, only IFN-gamma, IL-12 and TGF-β were noticeable on days 7 and 15, whereas in the lymph nodes draining the inoculation site positive expression of IL-2, IL-4, IL-12 and TGF-beta were found to be induced as soon as 24 h after re-entry of parasite. In the heart, the inflammatory response increased immediately 24 h after re-entry of parasites, reaching its maximum on the 7th day and returning to baseline on day 30. In conclusion, although the inflammatory response is triggered in both compartments by re-entry of parasites, the inflammatory process returns almost to baseline after 30 days, leaving a persistent low-grade inflammation.