BACKGROUND: In Egypt, the highly pathogenic avian influenza (HPAI) subtype H5N1 is endemic and possesses a severe impact on the poultry. To provide a better understanding of the distributional characteristics of HPAI H5N1 outbreaks in Egypt, this study aimed to explore the spatiotemporal pattern and identify clusters of HPAI H5N1 outbreaks in Egypt from 2006 to 2017. RESULTS: The Epidemic curve (EC) was constructed through time series analysis; in which six epidemic waves (EWs) were revealed. Outbreaks mainly started in winter peaked in March and ended in summer. However, newly emerged thermostable clades (2.2.1.1 and 2.2.1.2) during the 4th EW enabled the virus to survive and cause infection in warmer months with a clear alteration in the seasonality of the epidemic cycle in the 5th EW. The endemic situation became more complicated by the emergence of new serotypes. As a result, the EC ended up without any specific pattern since the 6th EW to now. The spatial analysis showed that the highest outbreak density was recorded in the Nile Delta considering it as the 'Hot spot' region. By the 6th EW, the outbreak extended to include the Nile valley. From spatiotemporal cluster epidemics, clustering in the Delta was a common feature in all EWs with primary clusters consistently detected in the hot-spot region, but the location and size varied with each EW. The highest Relative Risk (RR) regions in an EW were noticed to contain the primary clusters of the next EW and were found to include stopover sites for migratory wild birds. They were in Fayoum, Dakahlia, Qalyobiya, Sharkia, Kafr_Elsheikh, Giza, Behera, Menia, and BeniSuef governorates. Transmission of HPAI H5N1 occurred from one location to another directly resulted in a series of outbreaks forming neighboring secondary clusters. The absence of geographical borders between the governorates in addition to non-restricted movements of poultry and low vaccination and surveillance coverage contributed to the wider spread of infection all over Egypt and to look like one epidemiological unit. CONCLUSION: Our findings can help in better understanding of the characteristics of HPAI H5N1 outbreaks and the distribution of outbreak risk, which can be used for effective disease control strategies.