Purpose: To investigate the prognostic factors for hand, foot and mouth disease (HFMD) based on MR characteristics. Material and Methods: MRI scans in 412 Severe HFMD between 2009 and 2014 were retrospectively evaluated. The patients who had the neurological signs were followed for 6 months to 1 year. According to the good or poor prognosis, two groups were categorized. The incidence of lesions in different sites between two groups were compared, and multivariate analysis were used to look for risk factors. Results: There were 347(84.2%) patients with good prognosis and 65(15.8%) with poor prognosis in the follow-up. There were a significantly higher rate of lesions involving the cerebral white substance, thalamus, medulla oblongata, pons, midbrain and spinal cord in the group of poor prognosis. Multivariate analysis showed 2 independent risk factors associated with poor prognosis: lesions located in medulla oblongata (P<0.015)and spinal cord(P<0.001), and lesions involving spinal cord on MRI was the most significant prognostic factor (OR ratio 29.11, P<0.001). Conclusion: Our findings suggested patients with above two risk factors may be close monitored for early intervention and meticulous management. For the children with the symptom of nervous system, it is strongly recommended for the MR examination.