Background: Nail changes, including onychomadesis (nail shedding) and Beau’s line, following hand-foot-mouth disease (HFMD) are a common emergence at the stage of late complications of HFMD. However, the exact mechanism is still unknown. Therefore, we conducted this study to elucidate the mechanism of nail changes following HFMD. Methods: We collected 11 patients suffering from onychomadesis following HFMD. Nail samples from all of them were collected. Real time reverse transcription polymerase chain reaction (RT-PCR) and sequencing for human enteroviruses (HEV) were performed. Throat swabs for RT-PCR and sequencing for HEV were performed for three cases. Results: RT-PCR demonstrated the presence of Coxackievirus A6 (CVA6) in nail samples from three patients and one with Echovirus. Conclusion: In conclusion, we believe that the major cause of onychomadesis following HFMD is that certain novel viruses, mostly CVA6, are virulent and may damage nail matrix. Direct injury caused by cutaneous lesions of HFMD around nail matrix is a minor cause. There are still other virulent HEV which may result in onychomadesis. In addition, the novel strain of CVA6 also causes atypical clinical presentations, such as adult involvement and delayed-onset palmar and plantar desquamation. Physicians should be familiar with atypical presentations caused by novel viruses to avoid misdiagnosis and even inform patients of the possibility of onychomadesis that may take place weeks later to reassure patients.