Influenza A viruses play a significant role in human and animal pathologies that cause epidemics and epizootics. Therefore, the development of new anti-flu drugs has become increasingly urgent. Deoxyribozymes can be considered as promising antiviral agents due to their ability to efficiently cleave RNA molecules with high specificity. In this study, a number of genomic sequences of the most relevant influenza A virus subtypes, i.e., H5N1, H3N2, and H1N1, were analyzed. Conserved regions were revealed in the five least variable segments of the fragmented viral RNA genome, and potential sites of their cleavage with 10-23 deoxyribozymes were determined. We designed and synthesized 46 virus-specific 33-mer deoxyribozymes with the general structure of 5'N₈AGGCTAGCTACAACGAN₉. Screening of the antiviral activity of these agents in combination with lipofectin on the Madin-Darby Canine Kidney cells infected with highly pathogenic avian influenza virus A/chicken/Kurgan/05/2005(H5N1) revealed 17 deoxyribozymes that suppressed the titer of virus cytopathicity by more than 2.5 log TCID₅₀/mL (i.e. the neutralization index of the virus was more than 300), five of which suppressed the virus titer by a factor of 1000 or more. The most active deoxyribozymes appeared to be specific to segment 5 of the influenza A virus genome, which encoded NP nucleoprotein.