Liposomes are nanocarriers able to solubilize and deliver a wide range of hydrophobic pharmaceuticals and to increase drug bioavailability. They show a natural tendency to hepatic accumulation, and thus represent an optimal drug delivery system for the treatment of liver diseases, including chronic virus hepatitis C. Silibinin, the main and more active component of the seed extract from Silybum Marianum, is a hydrophobic flavolignan emerging as an alternative medication for the treatment of hepatitis C virus infection, as it has been shown to inhibit hepatitis C virus entry and replication. In this study we compared cellular delivery and antiviral activity of silibinin encapsulated into phytoliposomes or not, used at the aim to overcome its poor water-solubility and bioavailability. First, it was confirmed the inhibitory activity manifested by lipid-free silibinin in preventing hepatitis C virus entry into the cells. Our data clearly demonstrated that phytoliposome-encapsulated silibinin was absorbed by the cells 2.4 fold more efficiently than the free molecule and showed a three hundreds fold more potent pharmacological activity. Moreover, we surprisingly observed that phytoliposomes themselves inhibited virus entry by reducing the infectivity of viral particles. Based on these observations, phytoliposomes used in this study might be proposed as a delivery system actively contributing to the antiviral efficacy of the encapsulated drug.