Dopamine (DA) has a role in the pathophysiology of schizophrenia and addiction. Imaging studies have indicated that striatal DA release is increased in schizophrenia, predominantly in the precommissural caudate (preDCA), and blunted in addiction, mostly in the ventral striatum (VST). Therefore, we aimed to measure striatal DA release in patients with comorbid schizophrenia and substance dependence. We used [(11)C]raclopride positron emission tomography and an amphetamine challenge to measure baseline DA D(2)-receptor availability (BP(ND)) and its percent change post-amphetamine (ΔBP(ND), to index amphetamine-induced DA release) in striatal subregions in 11 unmedicated, drug-free patients with both schizophrenia and substance dependence, and 15 healthy controls. There were no significant group differences in baseline BP(ND). Linear mixed modeling using ΔBP(ND) as the dependent variable and striatal region of interest as a repeated measure indicated a significant main effect of diagnosis, F(1, 24)=8.38, P=0.008, with significantly smaller ΔBP(ND) in patients in all striatal subregions (all P0.04) except VST. Among patients, change in positive symptoms after amphetamine was significantly associated with ΔBP(ND) in the preDCA (r(s)=0.69, P=0.03) and VST (r(s)=0.64, P=0.05). In conclusion, patients with comorbid schizophrenia and substance dependence showed significant blunting of striatal DA release, in contrast to what has been found in schizophrenia without substance dependence. Despite this blunting, DA release was associated with the transient amphetamine-induced positive-symptom change, as observed in schizophrenia. This is the first description of a group of patients with schizophrenia who display low presynaptic DA release, yet show a psychotic reaction to increases in D(2) stimulation, suggesting abnormal postsynaptic D(2) function.Molecular Psychiatry advance online publication, 7 August 2012; doi:10.1038/mp.2012.109.