Hepatitis C virus (HCV) is predominantly a hepatotropic virus. Nonetheless, there is mounting evidence that hematopoietic cells may support HCV replication. The HCV 5' untranslated region (5'UTR), responsible for initiation of viral translation, via an internal ribosome entry site (IRES), has been previously described to contain specific nucleotide substitutions when cultured in infected lymphoid cells. Our purpose was to establish whether the 5'UTR polymorphism of quasispecies from 3 cell compartments (liver, peripheral blood mononuclear cells [PBMG], and monocyte-derived dendritic cells [DCs]) of a patient chronically infected with HCV1b affects the corresponding translational efficiencies and thus the capacity for replication. The 5'UTR polymorphism was characterized by identification of changes at 3 crucial sites as compared with the reference nucleotide (nt) sequence: a G insertion between positions 19 and 20, a C>A substitution at position 204 and a G>A substitution at position 243. The quasispecies detected in DCs was unique and differed from those present in the liver, suggesting a particular tropism of HCV quasispecies for DCs. Moreover, its translational activity was significantly impaired when compared with those from liver and PBMCs in different cell lines. This impairment was thoroughly confirmed in primary cultures of both human hepatocytes and monocyte-derived DCs. Taken together, our data lend support both to a specific location and impaired replication of HCV quasispecies in DCs, which could be related to viral persistence and perturbation of DC function in chronically infected patients.