The burden of sexually transmitted infections (STIs), such as syphilis, is higher in lowincome countries, with serious consequences and profound impact on sexual and reproductive health and human immunodeficiency virus (HIV) spread. Syphilis prevalence tend to be higher among people who misuse drugs than in the general population. To assess syphilis and associated factors among polydrug users (PDU) in the city of Salvador, Northeast Brazil. A cross-sectional study was conducted in 10 Brazilian cities between September and November 2009 using Respondent Driven Sampling (RDS). Participants answered an Audio Computer-Assisted Self Interview (ACASI) and were rapid tested for HIV and syphilis. We performed multivariable regression models for correlates of syphilis on Stata 10.0. Estimates were weighted by the inverse size of the individual social network size and homophily. Mean age was 29.3 years (range: 18–62), 74.0% were males, and 89.8% were non-white. Syphilis prevalence was 16.6%. Females (adjwOR:2.14; 95%CI:1.09–4.20), individuals over 29 years old (adjwOR:4.44; 95%CI:2.41–8.19), those who exchanged sex for money or drugs (adjwOR:3.51; 95% CI:1.84–6.71), “No/low” self-perceived risk of HIV infection (adjwOR:5.13; 95%CI:1.36–19.37), and having nine or less years of education (adjwOR:2.92; 95%CI:1.08–7.88) were associated with syphilis. One of the most pressing needs for syphilis prevention/control is the availability of rapid point-of-care diagnostic tests and treatment. Interventions should be tailored to PDU needs and their multiple burdens as shown in the present study, that may contribute to future studies aiming to better understand the relationships between drug use and syphilis.