The present study evaluated the effects of psychiatric comorbidity on substance use disorder prevalence, HIV risk behavior, and other problem severity in male and female out-of-treatment injection drug users newly registered at a syringe exchange program. Participants (N = 338) were administered the Structured Clinical Interview for the DSM-IV, the Addiction Severity Index, and the Risk Assessment Battery, and classified into one of four diagnostic groups: (1) no antisocial personality disorder (APD) or Axis I psychiatric disorder (N = 162), (2) APD only (N = 74), (3) Axis I psychiatric disorder only (N = 55), or (4) APD plus Axis I psychiatric disorder (N = 47). Psychiatric comorbidity was associated with higher rates of substance use disorder and more HIV risk and other problem severity. In general, participants with both APD and an Axis I disorder exhibited the most problem severity. APD was uniquely associated with higher prevalence for each substance use disorder assessed in this study and with elevated HIV risk. These results support and extend studies conducted with opioid-dependent individuals recruited from treatment and community settings, and reinforce the need to develop interventions to encourage syringe exchange program participants to enroll in treatment.