CD4+CD25+ T cells play a major role in modulating immune response, but few reports have been published about schistosomiasis. Here, we investigated the changes in CD4+CD25+ T cell populations in spleens and mesenteric lymph nodes of mice infected with Schistosoma japonicum. The proportions of CD4+CD25+ T cells in total CD4+ T cells were analyzed by flow cytometry. CD25 and Foxp3 expression was measured by real-time quantitative polymerase chain reaction. The suppressive activities of CD4+CD25+ T cells were detected by in vitro proliferation of splenocytes. Evidence showed that the percentage of CD4+CD25+ T cells was the same as controls 3 weeks post-infection. At the acute stage of infection, the percentage decreased significantly. However, at the chronic stage of infection, it rebounded to normal levels or even higher. The expression of the CD25 and Foxp3 showed gradual increase along with the infection progress. In vitro experiment also showed the strong suppressive effect of CD4+CD25+ T cells, isolated during the chronic stage, on proliferation of the CD25- splenocytes. This is the first time that the dynamics of CD4+CD25+ T cell populations was demonstrated in mice infected with schistosomiasis. In conclusion, our data indicated that CD4+CD25+ cells might be involved in the immune modulation during S. japonicum infection, which enhances current knowledge of the mechanisms of the immuno-downregulation and re-infection in schistosomiasis.