Current inactivated influenza vaccines can provide protection when vaccine antigens and circulating viruses share a high degree of similarity in hemagglutinin (HA) protein. Five antigenic sites in hemagglutinin protein have been proposed and 20 amino acid (AA) positions in the five antigenic sites have been mapped to bind with mouse monoclonal antibodies. However, the significance of these AA positions in polyclonal response is unclear. This study is to develop bioinformatics models combining ferret antibody cross-reactivity and virus AA sequence data to identify potential immunodominant AA positions in hemagglutinin protein. One hundred thirty-eight pairwise comparisons on antibody cross-reactivity and AA changes among 33 influenza H3N2 viruses were available. AA changes were found in 79 positions and 22 of the 79 positions were identified to be statistically associated with ferret antibody cross-reactivity (P<0.05). Effects of these 22 positions need to be verified experimentally using virus variants with point mutations.