Background Congenital syphilis incidence has more than tripled in recent years, in parallel with the resurgence of syphilis among reproductive-aged women. An understanding of risk factors associated with maternal syphilis infection can guide prevention of congenital syphilis through prenatal diagnosis and treatment. We aimed to describe factors associated with maternal syphilis and congenital syphilis at a public medical center in Chicago, Illinois. Methods Maternal syphilis diagnoses were identified using a database for local health department reporting. Medical records were reviewed for infant congenital syphilis diagnoses, sociodemographic information, medical history, and other behavioral factors. Maternal characteristics associated with congenital syphilis were assessed using logistic regression. Results Of 106 maternal syphilis diagnoses between 2014-2018, 76 (72%) had a known pregnancy outcome; of these, 8 (11%) delivered an infant with congenital syphilis. Women with psychiatric illness and non-injection substance use each had over a five-fold increased odds of having an infant with congenital syphilis. Cases with congenital syphilis were more likely to have late or scant prenatal care and initiated treatment nearly three months later in pregnancy. None were HIV positive or reported incarceration, intravenous substance use, sex work, or having sex with MSM. Conclusion Maternal psychiatric illness and substance use may have complicated prenatal care and delayed syphilis treatment, describing a population in need of public health intervention. Women experiencing such barriers to care may benefit from closer follow-up after a prenatal syphilis diagnosis to prevent congenital transmission.