The principal finding of this study is that rationally designed siRNA targeting influenza M2 gene (M-950) conferred effective long term inhibition against influenza A virus replication. Such high suppressive effect is not only against H1N1 influenza A virus but also against a highly pathogenic H5N1 subtype. In the previous related studies, Ge and his co-workers [25] screened siRNAs targeting to 6 conserved genes of influenza A virus and showed that NP-1496 was the best since it can confer a more than 200-folds inhibition of H1N1 virus. Li et al [29] and Tomkines et al [23] further confirmed that NP-1496 provided high anti-H5N1 effect. We therefore included NP-1496 as a positive control in this study. Our results showed that siRNA M-950 exhibited similar (Fig. 1 ) or even slight higher (Fig. 2) inhibitory effect against IAV replication as compared to that of NP-1496. A recent report by Zhou et al [30] also showed that several siRNAs targeting NP and M genes exhibited effective inhibition against influenza A virus replication in cultured MDCK cells and in animal models. However, sequences of their reported siRNAs targeting M2 gene are completely different from the siRNA M2-950. Furthermore, chemically synthesized siRNAs or plasmid based shRNAs were always delivered by transfection in previous related studies, whereas we used a lentivirus system to deliver selected shRNAs. Although the integration property of lentivirus has abrogated it to be used in human, it is helpful for our study purpose to successfully establish stable cell lines persistently expressing siRNAs.