Avian influenza viruses preferentially use alpha2,3-linked sialic acid as a receptor for binding and entry into target cells. The sialic acid is the terminal residue of various types of glycan. There are two major types of alpha2,3-linked sialic acid differing in the penultimate bond: Neu5Acalpha2-3Galbeta1-3GalNAc and Neu5Acalpha2-3Galbeta1-4GlcNAc. In the human airway, while Neu5Acalpha2-3Galbeta1-3GalNAc is present only in alveolar epithelial cells, the Neu5Acalpha2-3Galbeta1-4GlcNAc is expressed in both the upper and lower airway. Previous data showed preferential binding of hemagglutinin from H5N1 highly pathogenic influenza virus to Neu5Acalpha2-3Galbeta1-4GlcNAc. We further show here that suppression of this sialic acid by siRNA against a sialyltransferase, ST3GAL4, can inhibit H5N1 avian influenza virus infection and that this gene is abundantly expressed in human pharynx, trachea and bronchus. These data suggest that the ST3GAL4 gene is responsible for biosynthesis of the viral receptor and may play a crucial role in infection of H5N1 avian influenza virus in humans.