Abstract: The present invention provides double-stranded RNA molecules that mediate RNA interference in target cells, preferably hepatic cells. The invention also provides double-stranded RNA (dsRNA) molecules that are modified to be resistant to nuclease degradation, which inactivates a virus, and more specifically, hepatitis C virus (HCV). The invention also provides a method of using these modified RNA molecules to inactivate virus in mammalian cells and a method of making modified small interfering RNAs (siRNAs) using human Dicer. The invention provides modified RNA molecules that are modified to include a dsRNA or siRNA wherein one or more of the pyrimidines in the RNA molecule are modified to include 2?-Fluorine. The invention also provides dsRNA or siRNA in which all pyrimidines are modified to include a 2?-Fluorine. The invention provides that the 2?-Fluorine dsRNA or siRNA molecule is further modified to include a two base deoxynucleotide “TT” sequence at the 3? end of the molecule.