A Taiwanese woman who had chronic infection of type II hepatitis C virus was superinfected by type III hepatitis C virus after blood transfusion. The subtypes of the hepatitis C virus were determined by direct sequencing of the envelope region of the viral genome in serial serum samples before and after transfusion. The original virus in the patient had a 95.6% homology to the Taiwanese isolate (a type II virus) by comparing nucleotide sequences of the envelope region. After transfusion, markedly elevated serum aminotransferase activities were noted and the virus sequenced showed only a 55.2% homology to the Taiwanese isolate but had a 88.9% homology to a Japanese isolate (a type III virus). After recovery from the acute episode, the newly introduced type III virus became undetectable and type II virus predominated again but with significant genetic variation in the follow-up samples as compared with the original type II virus. It was concluded that superinfection of hepatitis C virus indeed occurs in humans, and this should be taken into consideration in the pathogenesis of reactivation of chronic type C hepatitis.