Syphilis, human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) share transmission routes. Syphilis infection can increase the risk of acquiring and transmitting HIV in key populations. The aims of this study were to investigate the risk factors and co-infection patterns for HIV, HBV and HCV in patients with syphilis. A retrospective study was conducted of 2,412 patients with syphilis (1,922 (79.68%) with latent syphilis, 336 (13.93%) with secondary syphilis, 78 (3.23%) with primary syphilis, 72 (2.99%) with tertiary syphilis, and 4 (0.17%) with congenital syphilis). Of these patients, 1,620, 1,427 and 1,374 were tested for HIV, HBV and HCV, respectively, with positive results in 8.21%, 5.75% and 1.02%, respectively. Multivariate logistic regression analysis found that male sex (adjusted odds ratio (AOR) 26.03; 95% confidence interval (CI) 10.37-65.36), age <55 years, especially age group 25-34-years (AOR 8.06; 95% CI 4.16-15.61), diagnosed at the Department of Infectious Disease (AOR 19.16; 95% CI 9.74-37.69), patients from Southern China (AOR 1.86; 95% CI 1.06-3.26) and having a rapid plasma reagin titre ≥1:32 (AOR 1.88; 95% CI 1.12-3.15) were independently associated with HIV infection. Risk factors for HBV co-infection in patients with syphilis, including male sex (AOR 1.78; 95% CI 1.12-2.83) and living in Southern China (AOR 4.66; 95% CI, 2.36-9.17) were also identified.