Data on treatment of patients with syphilis were reviewed in preparation for revision of the Sexually Transmitted Disease Treatment Guidelines of the Centers for Disease Control and Prevention. Published studies of treatment regimens available and practical for use today were reviewed, particularly in regard to the following issues: treatment for primary, secondary, and latent stages of syphilis; treatment for syphilis during pregnancy; treatment for syphilis in human immunodeficiency virus (HIV)-infected patients; and serological criteria for evaluating response to treatment. The results of treatment and the methodological quality of the studies was considered. Most treatment recommendations must be based on expert judgment and with reliance on the clinical experience over 4 decades. For the treatment of early syphilis in HIV-uninfected patients, this is probably sufficient. Data about HIV-infected patients are insufficient both for determining whether current therapy is adequate and for recommendation of an alternative if a change in therapy is deemed necessary.