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The CRF02_AG and sub-subtype A6 are currently the predominant HIV-1 variants in the Republic of Uzbekistan, but little is known about their time-spatial clustering patterns in high-risk populations. We have applied molecular evolution methods and network analyses to better understand the transmission patterns of these subtypes by analyzing 316 pol sequences obtained during the surveillance study of HIV drug resistance. Network analysis showed that about one third of the HIV infected persons were organized into clusters, including large clusters with more than 35 members. These clusters were composed mostly of injecting drug users and/or heterosexuals, with women having mainly high centrality within networks identified in both subtypes. Phylogenetic analyses of the ‘Uzbek’ sequences, including those publicly available, show that Russia and Ukraine played a role as the main sources of the current subtype A6 epidemic in the Republic. At the same time, Uzbekistan has been a local center of the CRF02_AG epidemic spread in the former USSR since the early 2000s. Both of these HIV-1 variants continue to spread in Uzbekistan, highlighting the importance of identifying transmission networks and transmission clusters to prevent further HIV spread, and the need for HIV prevention and education campaigns in high-risk groups.