This study analysed the spatio-temporal distribution and propagation of hand-foot-and-mouth disease (HFMD) in Shenzhen from 2008 to 2010. Specifically, we examined the epidemiological data, temporal distribution and spatial distribution, and then the relationship between meteorological, social factors and the number of reported HFMD cases was analysed using Spearman's rank correlation. Finally, a geographically weighted regression model was constructed for the number of reported HFMD cases in 2009. It was found that three independent variables, i.e. the number of reported HFMD cases in 2008 and, annual average temperature and precipitation, had different spatial impacts on the number of reported HFMD cases in 2009. In addition, these variables accounted for the propagation mechanism of HFMD in the centre and east of Shenzhen, where the high incidence rate areas are located. These results will be of great help in understanding the spatio-temporal distribution of HFMD and developing approaches to prevent this disease.