Humans chronically infected with Schistosoma mansoni most commonly present with the relatively asymptomatic intestinal form of the disease, whereas a small minority develop hepatosplenism characterized by severe hepatic disease with portal hypertension. Investigation of hypotheses describing the pathogenic mechanisms underlying the clinical forms of the human disease has been limited by the absence of an animal model that predictably develops such a spectrum of disease. We report that inbred male CBA/J mice that are chronically infected with S. mansoni develop two distinct syndromes, hypersplenomegaly syndrome (HSS) and moderate splenomegaly syndrome (MSS). Pathologically and immunologically, MSS and HSS remarkably parallel the intestinal and hepatosplenic clinical forms, respectively, in humans. HSS affects approximately 20% of these mice and consists of massive splenomegaly, ascites, thymic atrophy, severe anemia, and cachexia. The remaining majority of mice with MSS develop moderate splenomegaly only. Histopathological features of HSS include 1) relatively extensive hepatic fibrosis and granulomatous inflammation, 2) splenic congestion, 3) lymph node plasmacytosis, and 4) worms and eggs in the pulmonary vasculature. Immunologically, the idiotypes present on antisoluble egg antigen antibodies from HSS mice are distinct from those from mice with acute infections or the chronic MSS infection. These idiotypic differences are similar to those observed in patients with intestinal and hepatosplenic forms of the disease and may have regulatory importance. Investigation of the cellular and molecular events that lead to the development of MSS and HSS may advance current understanding of the pathogenesis of the clinical forms of chronic schistosomiasis in humans.