Background: Compared to the general population, drug users are at increased risk of both poor mental health and HIV infection. The aim of this study was to determine the prevalence and correlates of high psychological distress among drug users in Cambodia. Methods: In April 2014, a two-stage cluster sampling method was used to randomly select 169 drug users from hotspots in Phnom Penh. Psychological distress was measured using General Health Questionnaire (GHQ-12). Bivariate and multivariable analyses were conducted to identify factors associated with levels of psychological distress among this population.Results: Our study found high prevalence of attempted suicide (15.3%), drug related arrests (46.2%), and incarceration (31.4%). Of the 169 participants, 42.0% were found to have high levels of psychological distress, indicating poor mental health. After adjustment, high levels of psychological distress were independently associated with suicidal ideation (p< 0.001), higher frequency of drug use (p= 0.02), sharing of needles or syringes (p= 0.005), and having been sent to a rehabilitation centre (p= 0.02). In addition, participants who perceived their overall health as being poor or very poor were more likely to have high levels of psychological distress (p= 0.002).Conclusions: Integration of mental health within HIV and needle and syringe exchange programmes is required to address psychological distress among drug users in Cambodia. Health system interventions, such as screening, referral, and training of health providers, need to be strengthened. In addition, interventions addressing social determinants of mental health and mitigation of frequent arrests and improving conditions in rehabilitation centres are required.