OBJECTIVE: To determine the relationship between personality disorders (PDs) and substance use severity, mental health symptoms and disorders and quality of life (QoL) among injecting drug users (IDUs). DESIGN, SETTING AND PARTICIPANTS: A cross-sectional study of 103 IDUs accessing a needle and syringe program and a primary health centre in Melbourne, Australia. MAIN OUTCOME MEASURES: Presence of PDs was assessed using the International Personality Disorder Examination ICD-10 Screener. Axis I mental health disorders, psychological distress and QoL were also assessed. RESULTS: Ninety per cent of participants scored positive for one or more PD. Having a Cluster A or Cluster B PD was associated with greater severity of substance use. The presence of a current mental health disorder was associated with all types of PD except dissocial PD. Only Cluster C PDs were associated with self-reported levels of psychological distress. Cluster C PDs were more strongly associated with substance use, mental health and QoL variables than Cluster A or B, although the number of PDs present had the strongest associations with these variables. CONCLUSIONS: IDUs had high rates of PD symptoms, which were associated with the presence of concurrent mental health disorders, more severe levels of psychological distress and substance use and low perceived QoL. IDUs require comprehensive models of care, including access to mental health practitioners with expertise in co-occurring disorders.