Psychoses correlated with substance abuse prove to be more common in cases involving cannabinoids, stimulants, hallucinogens, and polyabuse. Among substance abusers, it has not been ascertained whether opioids exert a psychotic effect; some authors have supported the view that opioids exert antidepressant and antipsychotic effects. To clarify the relationships between opioids and psychosis, 23 psychotic heroin-dependent patients, at their first agonist opioid treatment, were compared with 209 nonpsychotic individuals in terms of their demographic and clinical characteristics. Psychotic heroin-dependent patients presented for agonist opioid treatment with more severe psychopathologic aspects and a shorter, less severe addiction history (except for polyabuse) than their nonpsychotic peers. The fact that our psychotic patients requested agonist opioid treatment earlier, and with a less severe addiction history, suggests that these patients may mainly benefit from an opioid medication through the improvement of their psychopathology, rather than through the alleviation of their heroin dependence. These data indirectly support the antipsychotic effects of opioid and Khantzian’s self-medication hypothesis for psychotic heroin-dependent patients.