BACKGROUND: Rates of early syphilis in US women are steadily increasing but predictors of infection in this group are not clearly defined. METHODS: This retrospective analysis focused on women enrolled in the US CFAR Network of Integrated Clinical Systems cohort between January 2005 and December 2016 with syphilis testing performed. The primary outcome of incident syphilis infection was defined serologically as a newly positive test with positive confirmatory testing after a negative test or a 2-dilution increase in RPR titer. Infection rates were calculated for each woman-year in care with testing. Predictors of syphilis were sought among socio-demographics, clinical information, and self-reported behaviors. Multivariable logistic regression models were created and a subgroup analysis assessed predictors in women of reproductive age. RESULTS: The annual rate of incident syphilis among 4416 women engaged in HIV care and tested during the 12-year study period was 760 per 100,000 person-years. Independent predictors of infection were injection drug use (IDU) as a risk factor for HIV acquisition (aOR 2.2, CI 1.3-3.9), hepatitis C infection (aOR 1.9, CI 1.1-3.4), black race (aOR 2.2, CI 1.3-3.7 compared to white race) and more recent entry to care (since 2005 compared to 1994-2004). Predictors were similar in women age 18-49. CONCLUSIONS: Syphilis infection is common among US women in HIV care. Syphilis screening and prevention efforts should focus on women reporting drug use and with hepatitis C co-infection. Future studies should identify specific behaviors that mediate syphilis acquisition risk in women who use drugs.