Hand, foot and mouth disease (HFMD) is a prevalent contagious childhood disease typically associated with fever, oral lesions and limb exanthema. While HFMD is caused by a plethora of serotypes of viruses under the genus Enterovirus within the Picornaviridae family, the most reviewed ones are Coxsackievirus A16 (CA16) and Enterovirus 71 (EV71) because they are considered to be the main etiological agents of HFMD. In recent years however, other viruses have also been isolated in considerable numbers from infected individuals in many regions, joining the legion commonly associated with HFMD. The present study investigated the cytokine and chemokine profiles of HFMD patients from Singapore and Malaysia for the first time. Our data revealed that the Malaysia cohort had a distinct profile from the Singapore cohort, and this could be partly attributed by different genotype of the same serotype (i.e. EV71) of HFMD etiological agents. As the isolation of CA6, instead of CA16, had become prevalent in the Singapore cohort in the recent years, it was also of particular interest to study the differential cytokine and chemokine profiles of the patients infected with CA6 in comparison to those infected with EV71. Our data revealed that overlapping as well as unique profiles exist among the different causative clinical isolates in the Singapore cohort. Having a better understanding of the respective immunological profiles could be useful for more accurate HFMD diagnosis, which is imperative for disease transmission control until multi-valent vaccines and/or broad-spectrum anti-viral drugs become available.