We have previously shown that the novel H7N9 virus, although replicating strongly in human DCs, did not efficiently induce antiviral IFN responses, and this deficiency was associated with a block in IRF3 activation. Interestingly, in H5N1 infection, in spite of the massive IFN induction the expression levels of IFN stimulated genes (ISGs) like MxA and IFITM3 remained relatively low. However, our new studies show that the H5N1 virus induces the robust IFN response by the incoming virus particles even if the virus replication is killed by UV treatment. By killing the H5N1 virus replication we were able to restore the expression of ISGs. Thus we further studied the role of the NS1 protein from different avian influenza viruses in antagonizing the IFN responses. We noticed that NS1 proteins from both H5N1 and H7N9 viruses were able to inhibit IFN-β promoter activation. Our data suggests that although both H7N9 and H5N1 avian-origin viruses cause severe pneumonia and ARDS in humans, the underlying mechanisms behind the pathology are distinct.