Description: Background: Guangzhou is the economic center of South China, which is currently suffering an insidious re-emergence of syphilis. Syphilis epidemic in this area is a matter of serious concern, because of the special economic position of Guangzhou and its large migrant population. Therefore, a comprehensive analysis of surveillance data is needed to provide further information for developing targeted control programs.MethodCase-based surveillance data obtained from a real-time, web-based system were analyzed. A hierarchical clustering method was applied to classify the 12 districts of Guangzhou into several epidemiological regions. The district-level annual incidence and clustering results were displayed on the same map to show the spatial patterns of syphilis in Guangzhou. Results: A total of 60,178 syphilis cases were reported during the period from 2005 to 2013, among which primary/secondary syphilis accounted for 15,864 cases (26.36 %), latent syphilis for 41,078 cases (68.26 %) and congenital syphilis for 2,090 cases (3.47 %). Moreover, primary/secondary syphilis burden slightly decreased from 17.5-18.0 cases per 100,000 people in the first years to 10.6 cases per 100,000 in 2013, with latent syphilis largely increasing from 18.5 cases per 100,000 to 43.4 cases per 100,000. Districts of Guangzhou could be classified into 3 epidemiological regions according to the syphilis burden over the last 3 years of the study period. Conclusions: The burden of primary/secondary syphilis appears to be decreasing in recent years, whereas that of latent syphilis is increasing. Given the epidemiological features and the annual changes found in this study, it is suggested that future control programs should be more population-specific and spatially targeted.