Background: People who use drugs are at a disproportionately higher risk of mental disorders due to prolonged exposure to psychosocial challenges. However, studies on mental health among people who use drugs in resource-constrained countries are scarce. This study sheds light on the prevalence and correlates of psychological distress among people who use drugs in Cambodia.Methods: We conducted this cross-sectional study in 12 provinces in 2017. The Respondent Driven Sampling method was adapted to recruit 1677 people who used drugs for face-to-face interviews using a structured questionnaire. Psychological distress was measured using the General Health Questionnaire (GHQ-12). A total score of GHQ-12>2 indicated high psychological distress. We performed a multiple logistic regression analysis to examine factors associated with psychological distress. Results: The mean age of the participants was 28.6 years (SD= 7.8). Of the total, 41.9% had high psychological distress – 49.7% in women and 37.3% in men. We included 1598 participants in the multiple logistic regression analysis. The adjusted odds of having high psychological distress was significantly higher among participants who were 25-34 years old (AOR 1.30, 95% CI 1.01-1.70) and 35 years and above (AOR 1.68, 95% CI 1.19-2.35), had been to a drug rehabilitation center (AOR 2.06, 95% CI 1.48-2.86), had been insulted by family members (AOR 2.09, 95% CI 1.62-2.70), and had been sexually harassed/abused by someone when they were growing up (AOR 1.80, 95% CI 1.38-2.36). The odds of having high psychological distress was significantly lower among participants who were male (AOR 0.53, 95% CI 0.41-0.69), lived in own dwelling (AOR 0.56, 95% CI 0.41-0.77), reported injecting as the mode of the first drug use (AOR 0.56, 95% CI 0.34-0.91), and had someone taking care of when getting sick (AOR 0.68, 95% CI 0.47-0.99).Conclusions: This study documents a high prevalence of psychological distress among people who use drugs in Cambodia. Intervention programs that attempt to address mental health problems among people who use drugs in resource-limited settings should be gender- and age-sensitive and target more marginalized subpopulations. Mental health services can be integrated into HIV and harm-reduction programs for people who use drugs.