Spatial distribution rules and risk factors for syphilis were studied in Jiangsu province, People's Republic of China during 2005 and 2009. Trend surface analysis, spatial autocorrelation analysis and spatio-temporal clustering were applied with the incidence rates of the various counties in the province to determine spatial distribution rules and risk factors. Syphilis was found to be most severe in the southern region of the province where many counties could be shown to be hotspots with positive autocorrelation. Clusters were detected in the south-western region of Jiangsu with the county-level city of Yixing as the centre. Temperature, distance from railways and highways, and the normalised difference vegetation index were determined as supporting variables with regard to the transmission of the disease by both univariate and multivariate spatial correlation analyses. Interventions, including health education and awareness campaigns, should be strengthened throughout the province targeting the south-western areas, especially the clusters and hotspots detected in order to improve the situation.