To elucidate determinants of morbidity in schistosomiasis mansoni, a community-based study was undertaken involving 2,451 subjects (mean age, 18.8 +/- 15.3 [SD] years) from four endemic sites in Ethiopia. Overall prevalence of infection was 65.9%, reported blood in stools was 35.8%, and schistosomal periportal thickening/fibrosis (PPT/F) was 4.6%. Similarly, 43.2% were positive for at least one marker of hepatitis B virus (HBV), 5.3% were HBsAg positive, and 1.3% were anti-hepatitis C virus (HCV) positive. Prevalence of PPT/F increased significantly with increasing community prevalence and intensity of S. mansoni infection. In a multiple logistic regression analysis, intensity of egg excretion, markers of HBV infection, age, and male sex were significantly associated with PPT/F, whereas co-infection with other intestinal helminths was associated with lower odds for PPT/F. HCV was not associated with S. mansoni infection or with schistosomal PPT/F. In conclusion, integrated helminth control targeting school-aged children, who have the highest burden infection, should be used to substantially reduce the risk of periportal fibrosis.