Three inactive monovalent EV-A71 vaccines have been launched in China since 2016, which may change the HFMD pathogen spectrum and epidemiological trend. Using notifications from the national surveillance system, we analyzed the epidemiological character profiles and the possible pathogen replacement. The proportion of HFMD cases aged 0-12 months decreased from 23.0% to 15.3% between 2013-2015 and 2017-2019 (p < 0.01). EV-A71 among laboratory-confirmed severe cases in 2013-2015 (62.8%) transformed to other EVs (67.2%) in 2017-2019. The age distribution of EV-A71 infection shifted to the older. The cumulative coverage of the EV-A71 vaccine for children aged six months to five years in Guangxi has increased, while in severe cases, the positive rate declined. After gradually expanded vaccination, EV-A71 associated incidence rate, case-severity rate has decreased, and other serotypes are becoming dominant. Thus, bivalent even polyvalent vaccines are urgently needed to control HFMD.