Despite universal prenatal syphilis screening recommendations and availability of effective antibiotic treatment, syphilis prevalence during pregnancy and the incidence of congenital syphilis have continued to increase in the United States (1,2). Concurrent increases in methamphetamine, injection drug, and heroin use have been described in women with syphilis (3). CDC used data on births that occurred during January 1, 2018-December 31, 2021, from two states (Arizona and Georgia) that participate in the Surveillance for Emerging Threats to Pregnant People and Infants Network (SET-NET) to describe the prevalence of substance use among pregnant persons with syphilis by congenital syphilis pregnancy outcome (defined as delivery of a stillborn or live-born infant meeting the surveillance case definition for probable or confirmed congenital syphilis). The prevalence of substance use (e.g., tobacco, alcohol, cannabis, illicit use of opioids, and other illicit, nonprescription substances) in persons with a congenital syphilis pregnancy outcome (48.1%) was nearly double that among those with a noncongenital syphilis pregnancy outcome (24.6%). Persons with a congenital syphilis pregnancy outcome were six times as likely to report illicit use of opioids and four times as likely to report using other illicit, nonprescription substances during pregnancy than were persons with a noncongenital syphilis pregnancy outcome. Approximately one half of persons who used substances during pregnancy and had a congenital syphilis pregnancy outcome had late or no prenatal care. Tailored interventions should address barriers and facilitators to accessing screening and treatment for syphilis among persons who use substances. The need for syphilis screening and treatment should be addressed at any health care encounter during pregnancy, especially among persons who use substances.