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Until 2010, HFMD was predominantly associated with enterovirus (EV) A71 and coxsackievirus (CV) A16 in Japan. In 2011, CV\u2010A6 emerged as a primary causative agent, causing the largest HFMD epidemic in Japan since 1981. Since then, CV\u2010A6 has caused large HFMD epidemics every 2 years. The phylogenetic analysis of complete Viral Protein 1 (VP1) sequences revealed that most CV\u2010A6 strains detected from 2011 to 2015 in Osaka City were classified into a different clade compared with CV\u2010A6 strains detected from 1999 until 2009. The majority of CV\u2010A6 strains detected in 2011 and most CV\u2010A6 strains detected from 2013 to 2015 were mainly divided into two distinct genetic groups. Each epidemic strain carried unique amino acid substitutions in the presumed DE, EF, and GH loops of the VP1 protein that is exposed on the surface of the virion. 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