Objective:To investigate the risk factors of hand foot and mouth disease(HFMD). Methods:Data collected through a prospective clinical study of HFMD conducted between 2008 and 2009 were examined to identify risk factors associated with neurological involvement in children with HFMD. Results:There were significantly differencs in listlessness,start,history of lethargy,total duration of fever≥3 days,peak temperature ≥38.5℃,vomit,headache,and absence of mouth ulcers. Listlessness was identified as an independent risk factor for neurological involvement in the analysis of 648 children admitted to hospital. Total duration of fever ≥3 days,peak temperature≥38.5℃,start,vomit,and listlessness had the sensitivity,specificity,positive predictive value (PPV) and negative predictive value(NPV) respectively:61.8%,80.2%,58.9%,82.0%;39.8%,88.4%,91.6%,31.6%;72.7%,80.2%,96.6%,90.3%;82.6%,76.4%,40.2%,95.8%;67.4%,90.2%,82.2%,80.4%. Conclusion:Listlessness,start,history of lethargy,total duration of fever ≥3 days,peak temperature≥38.5℃,vomit,headache,and absence of mouth ulcers were identified as clinical risk factors to help detect children at risk of neurological involvement. These risk factors may serve as a guide to clinicians to decide the need for hospitalization,further investigation,close monitoring for disease progression,and decrease of mortality in children with HFMD.