Enterovirus 71 (EV71) is one of the main etiological agents for Hand, Foot and Mouth Disease (HFMD) which have been shown to be associated with severe clinical manifestation such as aseptic meningitis, brainstem and cerebellar encephalitis leading to cardiopulmonary failure and death. Currently, due to a lack in understanding of EV71 pathogenesis, there are no therapies or vaccines approved by the United States Food and Drug Administration (FDA) to prevent HFMD infections. There is therefore a need to gain a better understanding of the mechanism of EV71 pathogenesis. The route of transmission was postulated that the virus transmit from one person to another through direct contact of vesicular fluid or droplet from the infected or via faecal-oral route. We have previously reported a human colorectal adenocarcinoma cell line (HT29) with epithelioid morphology as a useful in vitro model to study the pathogenesis of EV71. To this end, transcriptomics profiling was employed to monitor changes during EV71 infection via human whole genome microarray. The results reveal altered expression of human genes involved in critical pathways including immune response and stress response. Specifically, type I, II and III interferons signalling pathways were significantly up regulated. Together, data from this study provide valuable insights on the host-pathogen interaction between human colorectal cells and EV71.