The existence of extrahepatic sites of hepatitis C virus (HCV) replication has been proposed as a mechanism responsible for the poor antiviral immune response found in chronic infection. Dendritic cells (DCs), as unique antigen-presenting cells able to induce a primary immune response, are prime targets of persistent viruses. From 24 blood samples obtained from HCV-seropositive patients, peripheral blood DCs (PBDCs) were purified. HCV genomic sequences were specifically detected by reverse-transcription polymerase chain reaction in 6 of 24 PBDC pellets, and replicative-strand RNA also was found in 3 of 24 cell purifications. Analysis of the HCV quasi-species distribution in the PBDC population of 1 patient showed the presence of a dominant variant different from that found in plasma with respect to the primary amino-acid sequence and physicochemical profile of the hypervariable region 1 of glycoprotein E2. These data strongly suggest that PBDCs constitute a reservoir in which HCV replication takes place during natural infection.