The present study evaluates the prevalence of psychiatric and substance use disorders in male and female intravenous opioid abusers participating at a community needle exchange program (NEP). All participants (n = 422) were administered the Structured Clinical Interview for the DSM-IV (SCID) for Axis I disorders and antisocial personality disorder (APD). Psychiatric and substance abuse comorbidity were highly prevalent. Major depression was the most common current and lifetime Axis I non-substance use disorder (6 and 21% of the sample, respectively); 37% were diagnosed with APD. Over 50% of the sample was diagnosed with at least one non-substance use Axis I disorder or APD. In addition to opioid dependence, cocaine dependence was the most prevalent current and lifetime substance use disorder (68 and 78% of the sample, respectively), followed by alcohol and cannabis dependence. Overall, participants reported a mean of over one current and over three lifetime substance use disorders in addition to opioid dependence. Women reported higher rates of post-traumatic stress disorder (PTSD), while men were more likely diagnosed with APD. Presence of a psychiatric disorder was associated with increased prevalence of substance use disorder for all drug classes. The high rates of comorbidity observed in this sample suggest that the harm reduction efforts of NEPs can be significantly enhanced through referral of participants to programs that treat substance use and/or other psychiatric disorders.