BACKGROUND: Until now there has been no data to show the effectiveness or benefits of screening for syphilis in gravidas in China. This study was to assess the effectiveness of a program preventing mother-to-child-transmission of syphilis and to reveal factors impacting the benefit. METHODS: A cohort of 159,017 gravidas were screened for syphilis by serologic methods and infected individuals were treated with 3 injections of 2.4 million units of benzathine penicillin in Shenzhen in 2005. The pregnancy outcomes were compared for this cost-effectiveness analysis in 2 scenarios, intervention with screening and treatment versus no intervention. RESULTS: Eight hundred twenty-seven pregnant women (0.52%) were diagnosed with syphilis and treated subsequently. Of these, 200 gestations ended in miscarriage. Four babies were diagnosed with congenital syphilis; 25 neonates with low birth weight; 1 died after birth. The total cost was $636,748. On average, every $770 identified 1 infected mother. Every $4391 prevented 1 congenital syphilis; every $5135 prevented 1 low birth weight; and every $7075 prevented 1 death. One disability adjusted life year could be saved by $215. In total the program reached a benefit to cost ratio of 21.76. Sensitivity analyses revealed that this ratio was mainly impacted by the prevalence of syphilis in pregnant women and the rate of miscarriage. CONCLUSIONS: Screening for antenatal syphilis combined with intervening during gestation is highly effective in China. Reducing the percentage of spontaneous/induced abortion would be one of the most effective methods of further increasing the benefits of this screening.