Introduction The burden of sexually transmitted infections (STIs), such as syphilis, is greatest in median and low-income countries with serious consequences to sexual and reproductive health and increased risk to HIV infection. The prevalence of syphilis among drug users is higher than in the general population. Our aim is to report the rate of syphilis seroreactivity and associated factors among polydrug users (PDUs) in Northeast Brazil. Methods A cross-sectional study recruited 424 PDUs in Northeast Brazil through respondent driven sampling in 2009. Data was collected data using audio computer-assisted self-interview and rapid tests used for syphilis screening. Multivariable logistic regression was used to estimate factors associated with syphilis seroreactivity. Estimates were weighted by the inverse of the participant social network size. Results Mean age was 29.3 years (range: 18–62), 74.0% were males, and 89.8% were non-white. Syphilis seroreactivity was 16.6%. Being female (wOR: 2.14, 95% CI: 1.09–4.20), over 29 years old (wOR: 4.44, 95% CI: 2.41–8.19), exchange sex for money or drugs (wOR: 3.51, 95% CI: 1.84–6.71), “No/low” self-perceived risk of HIV infection (wOR: 5.13, 95% CI: 1.36–19.37), and having nine or less years of education (wOR: 2.92, 95% CI: 1.08–7.88) were associated with syphilis seroreactivity. Conclusion One of the most urgent needs for syphilis prevention and control is the availability of rapid point-of-care diagnostic tests and treatment, including the integration of STIs services into primary health-care and HIV-care/prevention settings. Gender issues, education in health, access to public services, social interventions focusing human rights, and social inequalities need more coverage for most at risk populations. Disclosure of interest statement This study was funded by the Brazilian Ministry of Health/Department of SDT/AIDS and viral hepatitis, with technical advisor from CDC Brazil. The first author is supported by a grant from the Brazilian National Research Council (CNPq) for his PhD studies.