The highly pathogenic avian influenza (HPAI) H5N1 virus has been circulating in Asia since 2003 and diversified into several genetic lineages, or clades. Although the spatial distribution of its outbreaks was extensively studied, differences in clades were never previously taken into account. We developed models to quantify associations over time and space between different HPAI H5N1 viruses from clade 1, 2.3.4 and 2.3.2 and agro-ecological factors. We found that the distribution of clades in the Mekong region from 2004 to 2013 was strongly regionalised, defining specific epidemiological zones, or epizones. Clade 1 became entrenched in the Mekong Delta and was not supplanted by newer clades, in association with a relatively higher presence of domestic ducks. In contrast, two new clades were introduced (2.3.4 and 2.3.2) in northern Viet Nam and were associated with higher chicken density and more intensive chicken production systems. We suggest that differences in poultry production systems in these different epizones may explain these associations, along with differences in introduction pressure from neighbouring countries. The different distribution patterns found at the clade level would not be otherwise apparent through analysis treating all outbreaks equally, which requires improved linking of disease outbreak records and genetic sequence data.