Background: Congenital syphilis (CS) occurs when an infected mother transmits syphilis to her infant during pregnancy and can be prevented through timely diagnosis and treatment of maternal infection. In the United States during 2012–2018, reported CS cases increased 291%. During 2018, 1,306 CS cases were reported, including 94 stillbirths and early infant deaths. We describe national and regional CS prevention opportunities to support development of a national CS prevention strategy. Methods: We reviewed 2018 national CS case report data, which includes information about infants with CS and their mothers. We calculated the proportion of mothers of infants with CS who received timely (≥30 days before delivery) prenatal care, syphilis testing, and penicillin-based treatment appropriate for maternal stage of syphilis. We then conducted stratified analyses and used chi-square tests to identify differences between the 2 highest case-count U.S. Census Bureau regions. Results: Of the 1,306 CS cases, 778 (59.6%) mothers of infants with CS had received timely prenatal care, and 822 (62.9%) had received timely testing, including testing outside of prenatal care. Additionally, 130 (9.9%) had documentation of timely, adequate treatment but delivered infants classified as CS cases because of such factors as reinfection or treatment failure. Most CS cases occurred in the South (52.5%) and West (35.6%), followed by 103 (7.9%) in the Midwest and 53 (4.1%) in the Northeast. In the South, 69.8% of mothers of infants with CS received timely prenatal care, compared with 44.3% in the West (P < .001). More mothers of infants with CS received timely syphilis testing in the South (73.3%) than the West (47.1%) (P < .001). In the South, 15.4% received timely, adequate treatment, compared with 5.2% in the West (P < .001). Conclusions: Nationally, opportunities exist for preventing CS by increasing timely prenatal care, testing, and treatment of maternal syphilis. Regional differences indicate different priorities for intervention. Ending the CS epidemic will likely require a national CS prevention strategy that acknowledges these differences.