Objective: To evaluate prospectively the Centers for Disease Control and Prevention (CDC) recommended regimens for the treatment of antepartum syphilis and prevention of congenital syphilis. Methods: This was a prospective evaluation of recommended syphilis treatment regimens from September 1, 1987, to August 31, 1989, at Parkland Memorial Hospital, Dallas, Texas. Women with syphilis were staged and treated according to CDC recommendations. Treatment included 2.4 million units of intramuscular (IM) benzathine penicillin G for primary, secondary, or early latent (less than 1 year) syphilis. Women with late latent (uncertain or longer than 1 year) syphilis were treated with 7.2 million units of benzathine penicillin G IM over 3 weeks. Results: During the study period, 448 of 28,552 women (1.6%) delivered were diagnosed with syphilis. One hundred eight were diagnosed at delivery and treated postpartum. The remaining 340 (75.9%) gravidas with untreated syphilis attending prenatal clinic comprised the study group. The success of therapy in preventing congenital syphilis was as follows: primary syphilis, 27 of 27; secondary syphilis, 71 of 75; early latent syphilis, 100 of 102; and late latent syphilis, 136 of 136. The success rate for all stages of syphilis was 334 of 340 (98.2%). The success rate of therapy in secondary syphilis was significantly different from that of the other groups (P = .03). Two of the six fetal treatment failures produced preterm stillborns. Only one maternal treatment failure occurred, in a human immunodeficiency virus-infected woman. Conclusion: The CDC-recommended regimens for the prevention of congenital syphilis and treatment of maternal infection are effective, but the highest risk of fetal treatment failure exists with maternal secondary syphilis. (Obstet Gynecol 1999;93:5-8.