In order to describe the trend of syphilis at the Infectious Diseases Clinic of Perugia University, Italy, over a six-year period (2005-2010), 138 patients were identified and monitored. Syphilis diagnosis was as follows: latent 60%, secondary 21%, neurosyphilis 10%, primary 9%. The study population comprised 83% males, 59% Italians and 45% men who have sex with men (MSMs). Heterosexual females represented 28.5% cases among immigrants and 8.5% cases among Italians, while men with unknown sexual contacts were 28% and 14% respectively (p=0.0059). HIV co-infection was detected in 70% of patients, with a predominance of males (94%) and Italians (62%). Among HIV-positive patients, 63% were pre-existing HIV-infected: of these, 26% had primary or secondary syphilis. During the study period, the number of regional syphilis notifications at the Italian Health Department was lower with respect to the observed cases at the Infectious Diseases Clinic of Perugia (69 versus 138). Globally, the trend of syphilis infection remained stable over the six-year period. However, efforts to improve prevention and screening programs are required for persons at risk of both syphilis and HIV infection, as well as measures to strengthen syphilis notification procedures.