Men who have sex with men (MSM), especially those with HIV-1 infection, are disproportionately affected by syphilis in higher income countries. The course, and some of the clinical features of the disease, especially the development of neurosyphilis, can be affected by HIV-1 co-infection. This review documents potential differences in the clinical features of syphilis in HIV-1 infected and uninfected MSM and highlights the importance of a thorough examination and high index of suspicion when seeing and treating MSM at risk of sexually transmissible infections.