Highly pathogenic avian influenza A virus (H5N1) has diverged antigenically and genetically since its initial detection in Asia in 1997. Viruses belonging to clade 2.2 in particular have been reported in numerous countries with the majority occurring in Egypt. Previous reports identified antigenic similarities between viruses belonging to clade 2.2. However, poultry and human viruses isolated in northern Egypt during 2007 and 2008 were found to be antigenically distinct from other clade 2.2 viruses from this country. Genetic analysis of the hemagglutinin revealed a high degree of nucleotide and amino acid divergence. The antigenic changes in Egyptian viruses isolated during 2007–08 necessitated that two of these strains be considered as potential H5N1 pre-pandemic vaccine candidates.