The Eurasian-lineage H5N1 highly pathogenic avian influenza (HPAI) virus caused widespread outbreaks in Egypt in 2006 and eventually become enzootic in poultry. Although outbreaks have a seasonal pattern, with most occurring during the cooler winter months, it remains unclear whether this seasonality reflects virus maintenance within Egypt or yearly introductions of the virus into the country. To evaluate the epidemiology of H5N1 HPAI in Egypt, sequence analysis of the hemagglutinin (HA) and neuraminidase (NA) genes of selected Egyptian isolates from early 2006 to 2008 was conducted. The data from this study identifies distinct genetic markers in both HA and NA genes and suggests grouping Egyptian isolates into two major HA isolate sublineages from 2006 to 2008 and into three smaller, emergent subgroups. The NA phylogenetic and sequence analysis showed a similar pattern, except that two of the emergent groups from the HA phylogenetic tree clustered together, evidence of likely reassortment. The different subgroups did not appear to segregate by relation to the date of isolation, to the species of origin, nor to the geographic location of the viruses. The conclusion is that H5N1 is continuing to mutate with multiple heterogenic strains persisting in Egypt.