Small interfering RNAs (siRNAs) and short hairpin RNAs (shRNAs) have been reported to suppress gene expression significantly. HCV seems a suitable candidate for targets of siRNAs, as HCV is a positive single-strand RNA virus and replicates in the cytoplasm. Efficient inhibition by siRNAs requires access to target RNAs, which usually possess secondary structure. We have shown that shRNAs suppressing the HCV internal ribosomal entry site (IRES) can inhibit different HCV genotypes grown in cell culture and replicon replication, suggesting the potential of siRNA as an additional therapeutic option against HCV infection.