Though syphilis can be controlled with penicillin and public health measures, an alternate method of control, such as vaccination, is still needed for the developing world and portions of the United States. We have expressed a series of recombinant proteins of Treponema pallidum, the spirochete bacterium that causes syphilis, that partially protect against challenge with T. pallidum. We used two techniques to identify these candidates: 1) an immunoscreen using serum that opsonizes T. pallidum for phagocytosis, and 2) a subtraction library approach, where sequences in common with T. pallidum and T. paraluiscuniculi (a closely related spirochete but not a pathogen of humans) were eliminated. Using these techniques, we identified three protective recombinant proteins: 1) Gpd: 2) D15/Oma87 homologue; and 3) TprK. All three of these proteins appear to be associated with the outer membrane of T. pallidum. Gpd has both glycerophosphodiester phosphodiesterase activity and immunoglobulin binding activiity. D15/Oma87 homologue is homologous to outer membrane proteins from H. influenza (D15) and N. gonorrhoeae (Oma87)that are protective against challenge in those systems. TprK is related to the major surface protein (msp) of Treponema denticola. Antibodies to D15/Oma87 homologue and TprK facilitate the opsonization of T. pallidum, supporting their surface localization on T. pallidum. Immunization with Gpd, D15/Oma87 homologue, or TprK partially protects rabbits against challenge with T. pallidum, in that lesion development is attenuated or absent and organism growth is severely impeded. These proteins are promising vaccine candidates for syphilis.