An outbreak of hand, foot, and mouth disease (HFMD) in Guangzhou in 2008 affected over 10,000 children and resulted in high hospital admission rates. To investigate the molecular epidemiological pattern of EV71 infections in Guangzhou, throat swab samples were collected from 102 children clinically diagnosed with HFMD from May to July of 2008 in Guangzhou. Partial VP1 (virus protein 1) fragments of Enterovirus 71 (EV71) isolates were sequenced, and used alongside EV71 sequences entered in GenBank to construct a phylogenetic tree using MEGA5.0. Blast and phylogenetic analyses showed that all 21 sequences belonged to subgenogroup C4 of EV71. In early May, diverse strains were circulating in Guangzhou, but by July, only a small number of these strains could be detected. These results could indicate that geographic and climatic features may affect the epidemic characteristics of EV71, and that some C4 strains might retain their infectivity at higher temperatures.