A new approach to anti-influenza chemotherapy is based on the development of synthetic inhibitors of virus attachment to host cells. These inhibitors are prepared by anchoring the minimum receptor determinant of influenza virus, sialic acid, to polymeric or liposomal carriers. In this study, a series of poly(acrylic acid-co-acrylamides) and dextrans bearing pendant glycylamidobenzylsialoside groups were synthesized and evaluated for their binding to a panel of influenza A and B virus strains and for their ability to inhibit virus infectivity in cell culture. Significant type-, subtype-, and strain-specific variation in virus susceptibility to the synthetic inhibitors was observed. Among the viruses tested, H3 subtype strains evolved in humans since 1975 were the most sensitive, while the earlier H3 viruses and the type B strains were resistant. The virus-inhibitory potency of the polymeric sialosides correlated with their bindings to the virus, and was dependent on the virus affinity for the ligand, the density of the ligand, and the nature and molecular mass of the polymeric carrier. In embryonated eggs, the antiviral effect of poly(acryloyl-glycylamidobenzylsialoside-co-acrylic acid) was comparable to that of equine alpha 2-macroglobulin.