Hand, foot and mouth disease (HFMD) is responsible for a heavy economic and social burden in the Asia-Pacific region. Previous studies have shown that coxsackievirus A6 (CVA6) and coxsackievirus A10 (CVA10) have become the predominant agents of HFMD in mainland China in recent years, replacing enterovirus 71 (EV71) and coxsackievirus A16 (CVA16), although it is unclear if this is consistent throughout China. In this study, samples from 253 HFMD cases were collected in Shenzhen, China, from May 2013 through April 2014 to identify the etiological agent of HFMD. In total, 64.8% (164/253) of HFMD cases were enterovirus positive, in which 81.1% (133/164) were determined to be CVA6. The phylogenetic tree of the partial viral protein 1 sequence showed that the CVA6 isolates were divided into four clusters (Clusters A to D), and cluster D was further divided into four sub-clusters (Clusters D1 to D4). The 133 CVA6 samples isolated in our study were classified into cluster D4, in which the first identified sequence was isolated in Shenzhen in 2008. This study demonstrated that the CVA6 cluster D4, which is predominantly circulating in HFMD in mainland China, may have originated from a local strain identified in 2008 in Shenzhen.