The purpose of this study was to examine the epidemiological profiles of hand, foot, and mouth disease (HFMD) activity in Suzhou, China, and the relationship between meteorological factors and enterovirus71 (EV71) and coxsackievirus A16 (CoxA16) infection. Children < 14 years old with probable HFMD at Soochow University Affiliated Children's Hospital were enrolled during January 2008 to December 2013. Samples from hospitalized children with HFMD were collected and tested using real-time reverse transcription PCR. Correlations between probable HFMD, laboratory-confirmed HFMD, and meteorological factors were analyzed using bivariate correlation, stepwise regression and time series analysis. A total of 29,530 probable cases were diagnosed with HFMD, and 1090 hospitalized cases were confirmed in the laboratory. The median age of individuals with HFMD was 28.6 months (interquartile range, 18-46.9 months), and the incidence was highest in children aged 12-36 months. Children infected with other enteroviruses were younger than those infected with EV71 and CoxA16. Mean temperature and total rainfall were strongly correlated with probable HFMD. In terms of the specific pathogen, only EV71 cases were associated with mean temperature during the study period of 2012-2013. Based on a simple seasonal model with a good fit, a seasonal pattern of HFMD activity could be predicted. This study provides quantitative evidence that probable HFMD was associated with mean temperature and total rainfall. Furthermore, a seasonal model could be used as an early and reliable monitoring system to predict seasonal pattern of HFMD in Suzhou, China.