In murine Schistosoma mansoni infections, schistosome-specific cross-reactive idiotypes (CRI) are present in the sera of mice with moderate splenomegaly syndrome (MSS) at 20 wk after infection. In contrast, sera from animals that have the more severe hypersplenomegaly syndrome (HSS) at 20 wk of infection do not express these CRI in their sera. To examine when these regulatory CRI first appear in mice that eventually develop MSS, sera from infected animals were monitored for CRI from 1.5 to 20 wk of infection. In mice that eventually developed MSS, CRI were detected by 5 to 6 wk after infection, plateaued by 8 to 10 wk, and persisted through 20 wk of infection. Animals that developed HSS pathology or that died before 20 wk of infection never expressed CRI. Moreover, CRI levels present in the sera of mice at 6 wk of infection were inversely correlated with splenomegaly and hepatic fibrosis, but not with parasitologic measures, at 20 wk after infection. These results suggest that critical events occur very early in some schistosome infections that induce the production of regulatory idiotypes and that the presence or absence of these idiotypes predicts, and possibly determines, subsequent morbidity.