The hemagglutinins of influenza viruses isolated from humans typically prefer binding to sialic acid in an alpha2,6 linkage. Presumably, the virus uses the presence of these receptors on the respiratory tract to gain entrance into the host cell. The ST6Gal I sialyltransferase knock-out mouse lacks the main enzyme necessary for the attachment of alpha2,6 sialic acid to N-linked glycoproteins on the cell surface. Yet even in the absence of detectable alpha2,6 sialic acid in the mouse respiratory tract, human influenza viruses can still infect these mice and grow to similar titers in the lung and trachea as compared to wild-type animals. This work demonstrates that the presence of a major alpha2,6 sialic acid on N-linked glycoproteins is not essential for human influenza virus infection in mice.