Syphilis is a prominent disease in low- and middle-income countries, and a re-emerging public health threat in high-income countries. Syphilis elimination will require development of an effective vaccine that has thus far remained elusive. Here we assess the vaccine potential of Tp0751, a vascular adhesin from the causative agent of syphilis, Treponema pallidum subsp. pallidum. Tp0751-immunized animals exhibit a significantly reduced bacterial organ burden upon T. pallidum challenge compared with unimmunized animals. Introduction of lymph nodes from Tp0751-immunized, T. pallidum-challenged animals to naive animals fails to induce infection, confirming sterile protection. These findings provide evidence that Tp0751 is a promising syphilis vaccine candidate.