Entry of the hepatitis C virus (HCV) into the cell seems to be a complex multi-step process involving several cellular factors such as the scavenger class B type I receptor (SRBI). Until now, all investigations conducted to assess the involvement of SRBI have been based on in vitro infection models which use human hepatoma-derived cell lines. However, the HCV entry pathway may be altered in these types of cells because of the impairment of some hepatic characteristics. In this study, we showed that SRBI also plays an essential role in HCV entry into primary human hepatocytes with two distinct approaches: gene extinction and antibodies neutralization assays.