We studied the evolution of the HA1 domain of the H3 hemagglutinin gene from human influenza virus type A. The phylogeny of these genes showed a single dominant lineage persisting over time. We tested the hypothesis that the progenitors of this single evolutionarily successful lineage were viruses carrying mutations at codons at which prior mutations had helped the virus to avoid human immune surveillance. We found evidence that eighteen hemagglutinin codons appeared to have been under positive selection to change the amino acid they encoded in the past. Retrospective tests show that viral lineages undergoing the greatest number of mutations in the positively selected codons were the progenitors of future H3 lineages in nine of eleven recent influenza seasons. Codons under positive selection were associated with antibody combining sites A or B or the sialic acid receptor binding site. However, not all codons in these sites had predictive value. Monitoring new H3 isolates for additional changes in positively selected codons might help identify the most fit extant viral strains that arise during antigenic drift.