Hand, foot, and mouth disease (HFMD) was one of the most common children illnesses. Coxsackievirus A16 was one of the major pathogens that cause HFMD. However, the role of vitamin D underlying this common illness has not been elucidated. Our study examined that vitamin D levels was significantly lower in 33 HFMD patients, compared to 36 healthy children. Unexpectedly, both mRNA and protein expression of VDR were significantly decreased in CA16 infected glioblastoma A172 cells. And over expression of VDR or vitamin D treatment in CA16 infected glioblastoma A172 cells could reverse the CA16 infection induced cell death, apoptosis or mitochondrial membrane rupture. Therefore, our study, for the first time, demonstrated that vitamin D and VDR could associate with the pathogenesis of HFMD. Thus might provide useful information for HFMD prevention and treatments. (C) 2017 Elsevier Inc. All rights reserved.