ObjectivesThis study investigated the genotype-specific dynamics of molecular HIV clusters (MHCs) in Guangzhou, China, aiming to enhance HIV control. MethodsHIV pol sequences from people with HIV (PWH) in Guangzhou (2008-2020) were obtained for genotyping and molecular network creation. MHCs were identified and categorized into three types: emerging, growing, or stable. Clustering rates, proportions of cluster types and members within each type were calculated and their trends were assessed using joinpoint regression. ResultsAmong 8,395 PWH, the most prevalent HIV-1 genotypes were CRF07_BC (39.7%) and CRF01_AE (32.6%). The genotype composition has been stable since 2012 (Ps>0.05). The overall clustering rate was 43.3%, with significant variations across genotypes (P<0.001), indicating genotype-specific transmission fitness. Significant declines in overall and genotype-specific clustering rates towards the end of 2020 (Ps<0.05), potentially offer support for HIV control efforts in reducing local infections. The continuously increasing proportions of stable clusters and the gradually decreasing proportions of emerging and growing clusters (either Ps<0.05 or Ps>0.05) suggests a trend towards stable molecular network structure. However, growing clusters exhibited CRF55_01B, CRF07_BC and CRF59_01B dominance that indicate their priority for interventions. ConclusionsThe evolving molecular HIV clusters highlight the genotype-specific cluster dynamics, providing fresh insights for enhanced prevention and control strategies.