Enterovirus 71 (EV71) infection may be asymptomatic or may cause diarrhea, rashes, and hand, foot, and mouth disease (HFMD). However, EV71 also has the potential to cause severe neurological disease. To date, little is known about the molecular mechanisms of host response to EV71 infection. In this report, we utilized cDNA microarray to profile the kinetics and patterns of host gene expression in EV71-infected human neural SF268 cells. We have identified 157 genes with significant changes in mRNA expression and performed hierarchical clustering to classify these genes into five different groups based on their kinetics of expression. EV71 infection led to increases in the level of mRNAs encoding chemokines, proteins involved in protein degradation, complement proteins, and proapoptotis proteins. cDNA microarray expression comparisons of EV71- and mock-infected cells also revealed the down-regulation of several genes encoding proteins involved in host RNA synthesis. Expression of interferon-regulated proteins was increased early in the infection and then decreased. Expression of proteins involved in cellular development and differentiation, some oncogenes, and transcription and translation regulators were suppressed and then stimulated late in the infection. Our findings illustrate the overall host response to EV71 infection, and will aid in understanding the host response to this virus.