To investigate the long term natural course of primary hepatitis C virus infection in children from the beginning, we prospectively followed up 88 children at risk because of frequent blood transfusions or of hepatitis C virus infection from the mother. Ten of the 88 children contracted primary infection during follow-up. In the acute stage of infection acute hepatitis with elevation of aminotransferases and a positive IgM antibody was found in both children infected during open heart surgery, 3 of the 5 multiply transfused children with congenital hemolytic anemia and none of the 3 infants infected by their mothers. Four of the 10 children later lost hepatitis C virus RNA, whereas 6 had a chronic course. Three of the latter 6 children had abnormal aminotransferase activities in the chronic phase. Our study suggests that the very young age of primary infection and the underlying status of the host may affect the clinical course of hepatitis C virus infection in children.