This cross-sectional study explored the prevalence and correlates of syphilis infection among people who use and inject drugs (PWUD/PWID) in Cambodia. Data were collected in 2017 from 1,677 PWUD/PWID living in the capital city of Phnom Penh and 11 other major provinces using the respondent-driven sampling method. The SD Bioline HIV/Syphilis Duo test was used to determine human immunodeficiency virus (HIV) and current or past syphilis infection. A multivariable logistic regression analysis was conducted to identify risk factors associated with current or past syphilis infection. The prevalence of current or past syphilis infection was 3.8% (95% confidence interval = 2.4-4.6). After adjustment, current or past syphilis infection remained positively associated with being female, living on the streets, having an average monthly income of US$100-299, having transactional sex in the past three months, and having been to a rehabilitation centre in the past 12 months. Current or past syphilis infection was negatively associated with having attained at least high school level of formal education. The findings indicate vulnerability to syphilis infection among PWUD/PWID in Cambodia, particularly among subpopulations who are more marginalized. Syphilis prevention and control programmes should be systematically integrated into HIV and sexually transmitted infection policy and services in the country.