Background: Children are the backbone of the nation. Among under-five children from the year 2012 to 2016, more than one million HMFD (hand, mouth, and foot disease) cases have been reported in India. HMFD is a viral infection caused mainly by Coxsackievirus-16 and sometimes Enterovirus-17. Materials and methods: The research design used for this study was a descriptive comparative research design. Sixty samples (30 mothers of under-five children and 30 staff nurses from pediatric ward) were selected by using purposive sampling technique. The study was conducted at pediatric ward at MGMCRI (Mahatma Gandhi Medical College and Research Institute) in Puducherry. Result: This result showed that knowledge regarding HMFD of the staff nurses is more than that of the mothers of under-five children and there is no significant association between the knowledge regarding the HMFD among the mothers of under-five children with selected demographic variables. Demographic variables of clinical experience and area of postings among staff nurses are statistically significant. Conclusion: There is a need to be aware of HMFD among the mothers of under-five children and nurses. Screening is necessary to detect the hand, mouth and foot disease among children.