Strengthening current surveillance systems for syphilis is important to track and monitor disease burden. We used routinely collected laboratory information to generate surveillance estimates for syphilis trends among women of reproductive age (12–49 years) in the Northern Cape Province, a high syphilis burden region (2003 [8.6%] to 2011 [3.8%]) in South Africa. We extracted records meeting inclusion criteria from the National Health Laboratory Service electronic database for the period 2003–2012. A total of 286,024 women were included in the analysis. Syphilis seropositivity decreased between 2003 (5.7%) and 2012 (1.8%); p trend = 0.001, which was largely consistent with findings reported in the annual national syphilis and HIV survey from 2003 (8.6%) to 2011 (3.8%). Annually for the period from 2003 to 2012 there was an approximate 14% reduction in the prevalence ratio of syphilis seroprevalence (PR = 0.86, 95% CI = 0.85–0.87, p < 0.001). Three of five districts had significant decreases in syphilis seropositivity over this period. There were also declines in prevalence ratios for syphilis seropositivity for the various age groups for the period. This study shows that the national laboratory database in South Africa can be used as a complimentary surveillance tool to describe and understand trends in syphilis seroprevalence in South Africa.