AbstractIntroduction and AimsPeople who use drugs (PWUD) face several mental health problems. This report aims to examine the prevalence of and factors associated with psychological distress among Cambodian PWUD.Design and MethodsData used in our analysis were from the national survey of 1626 PWUD recruited through respondent‐driven sampling method in Cambodia in 2012 to 2013. Distress was measured through self‐report by using the 10‐item Kessler Psychological Distress Scale (K10). All analyses were weighted.ResultsApproximately half of PWUD had mild to severe psychological distress in the past four weeks (K10 ≥ 20). In the adjusted analysis, being female (odds ratio 1.60; 95% confidence interval 1.22, 2.12) and having experienced living in rehabilitation centres (odds ratio 2.46; 95% confidence interval 1.56, 3.87) were associated with a higher risk of having moderate or severe psychological distress (K10 ≥ 25).Discussion and ConclusionsPsychological distress was prevalent among Cambodian PWUD. PWUD who were female or experienced living in rehabilitation centres were more likely to report distress. Policy makers should consider shifting further from compulsory institutionalised treatment model to community‐based treatment program. Mental health assessment and mental health care services should be included in drug treatment programs and should be gender‐sensitive. Further research investigating other mental disorders among PWUD are also needed.