A histopathological and immunophenotypic study was performed on the spleen of patients with hepatosplenic (HS) schistosomiasis mansoni. Morphological data demonstrated that all HS patients presented features related to Schistosoma mansoni-induced splenomegaly, such as red pulp congestion and atrophy/hyperplasia of white pulp. The morphological diversity of the white pulp seems to be associated with the expansion of activated CD4+ T-cell subpopulation. The data obtained suggest that the spleen is an important site for T-cell activation during severe chronic infection with S. mansoni. In addition, we have compared the cell populations/subpopulations presented in the peripheral blood with that observed in the spleen of patients with HS schistosomiasis mansoni. We observed a significant increase in the percentage of activated CD4+HLA-DR+ and CD8+HLA-DR+ T cells in both the spleen and the peripheral blood of HS patients in comparison with noninfected individuals (NOR). These data suggest an exchange of cells between these two compartments. However, we observed normal expression of the CD28 molecule by CD8+ T cells in the spleen, despite a lower percentage of these cells in the peripheral blood. This finding supports the hypothesis that the decrease in CD28 expression, by CD8+ cells, is an event that takes place outside the spleen during human schistosomiasis infection. The most important conclusion is the fact that the analysis of T-cell activation in the peripheral blood reflects the major immunological reactivity that occurs in the spleen during human schistosomiasis and that the morphological aspects of the spleen may reflect the functional activity of T cells. The specificities of T cells and the roles they may play in the pathogenesis during chronic schistosomiasis now need to be determined.