The spleen is an important immunologically active compartment, where cells from the immune system interact with parasite-derived antigens during Schistosoma mansoni infection. Morphometric and structural changes in the spleen as well as alteration on its cellularity during chronic infection might be associated with the clinical findings on the hepatosplenic disease. Some morphologic aspects of the splenomegaly, profile of cell phenotype during severe chronic infection, dynamic aspects of possible explanations of the hepatosplenic disease development are discussed. This review will attempt to summarize these findings during human chronic schistosomiasis and discuss how they may contribute to the clinical manifestations observed in the hepatosplenic disease.