In March 2016, a cluster of unexplained respiratory illnesses was reported by the acute respiratory infections (ARI) surveillance system of Guangdong Province, China. Twenty-three high school students and one teacher from the four neighboring classes were admitted to a hospital. CVA21 was found in eight of fourteen patients. Phylogenetic analysis suggested that the CVA21 outbreak was most likely caused by transmission of the virus from person to person. This is the first report of an ARI outbreak caused by CVA21, which suggests that CVA21 has the potential to be transmitted efficiently from person to person and should be closely monitored by clinicians and public health agencies.