Human H3 strains of influenza A virus preferentially bind cell-surface oligosaccharides containing the sequence NeuAc alpha 2,6Gal, while avian influenza strains preferentially recognize the sequence NeuAc alpha 2,3Gal. The distribution of these two types of sialic acid linkages on host respiratory epithelium, the target of influenza infection, may be a factor in the selection of the different receptor specificities observed in human and avian influenza strains. To examine the distribution of these two structures on human tracheal epithelial cells, two sialic acid specific lectins were used. The Sambucus nigra lectin (SNA), which recognizes the sequence NeuAc alpha 2,6Gal/GalNac, primarily binds to the surface of the ciliated tracheal epithelial cells, and only weakly binds to mucins in the surface goblet cells. In contrast, the Maackia amurensis lectin (MAL), which is specific for the NeuAc alpha 2,3Gal sequence, binds strongly to mucus droplets in goblet cells, but not to the surface of ciliated cells. Thus, human ciliated tracheal cells appear to contain sialyloligosaccharides preferentially recognized by human influenza strains. These findings suggest that human H3 influenza strains may have evolved a receptor specificity which favors binding to ciliated cells, and minimizes binding inhibition by respiratory mucus.