Hepatitis C virus (HCV) has been reported to potentially replicate in peripheral blood mononuclear cells (PBMCs), but direct information on the pathogenic implication of HCV infection in PBMCs is still limited. To investigate this issue, we compared the complexity of HCV quasispecies in serum, PBMCs, and livers of 13 patients with type C chronic liver disease. Hypervariable region 1 (HVR 1) was amplified by reverse-transcription polymerase chain reaction (RT-PCR), and the PCR products were subcloned and sequenced. Considerable differences in the complexity of HVR 1 quasispecies were found in the serum, PBMCs, and liver in all patients, and the predominant sequences from each source were mutually different in 3 (23%) patients. An amino acid sequence unique to each source existed as well as a sequence common to serum and PBMCs, common to serum and livers, or common to PBMCs and liver. These results suggest infection of PBMCs by HCV, and that HCV in PBMCs may be differently exposed to host immunity from that in liver.