BACKGROUND: The lifetime prevalence of substance use disorders among schizophrenia patients is close to 50%. The negative consequences of substance abuse in schizophrenia are well documented, but the etiology of this comorbid condition remains unknown. According to the affect regulation model, schizophrenia patients abuse drugs in order to cope with their negative affects. Supporting the model, clinical studies have shown that dual-diagnosis patients have less blunting of affect and that they experience more negative affect. We hypothesized that patients with a history of substance use would have increased cerebral activations in response to aversive stimuli when compared to abstinent patients. METHOD: Schizophrenia patients were divided into 2 groups: patients with (SCZ-SU group; N = 12) and without (SCZ group; N = 11) a current or past substance use disorder (alcohol, cannabis, and/or LSD). Diagnoses were made according to DSM-IV criteria. Using functional magnetic resonance imaging (fMRI), patients were scanned during passive viewing of emotionally negative pictures (International Affective Picture System). Data were gathered from September 2001 to December 2003. RESULTS: Subjectively, the emotional experience induced by viewing the negative pictures was rated significantly higher in the SCZ-SU group than in the SCZ group (p = .008). Neurally, in the SCZ-SU group, significant loci of activation were identified in the right medial prefrontal cortex (Brodmann's area [BA] 10), left medial prefrontal cortex (BA 10), right orbitofrontal cortex (BA 47), and left amygdala. No significant loci of activation were observed in the SCZ group. CONCLUSIONS: These results suggest that the functioning of the medial prefrontal cortex, thought to be impaired in patients with prominent negative symptoms, is more preserved in dual-diagnosis schizophrenia. This relative preservation could be primary or secondary to substance use.