Previous studies have shown that apolipoprotein C1 (apoC1)-specific antibodies precipitated hepatitis C virus (HCV) and neutralized HCV infectivity, suggesting that apoC1 is a HCV component. However, the importance of apoC1 in the HCV life cycle has not been experimentally examined. In the present study, we sought to determine the role of apoC1 in the HCV infection and morphogenesis by knocking out the apoC1 gene using the CRISPR/Cas9 system. Strikingly, apoC1 gene knockout markedly enhanced apoE expression. As a result, apoC1 gene knockout per se didn't significantly affect HCV infection or morphogenesis, probably ascribing to its redundant functions with apoE. However, knockout of apoC1 gene potentiated the impairment of HCV infection and/or morphogenesis by apoE-specific small interfering RNAs. Additionally, a recombinant apoC1 protein efficiently blocked HCV infection. Collectively, these findings suggest that apoC1 and apoE have redundant functions in the HCV infection and morphogenesis.