The replicative properties of influenza hemagglutinin (HA) mutants with altered receptor binding characteristics were analyzed following intranasal inoculation of mice. Among the mutants examined was a virus containing a Y98F substitution at a conserved position in receptor binding site that leads to a 20-fold reduction in binding. This mutant can replicate as well as WT virus in MDCK cells and in embryonated chicken eggs, but is highly attenuated in mice, exhibiting lung titers over 1000-fold lower than WT. The capacity of the Y98F mutant to induce antibody responses and the structural locations of HA reversion mutations are examined.