Numerous studies have implicated the endocannabinoid system in the pathophysiology of schizophrenia. Endocannabinoids have been measured in blood and cerebrospinal fluid in schizophrenic patients but, to the date, there are no published reports dealing with measurements of endocannabinoid levels in schizophrenics' brain tissue. In the present study, postmortem brain samples from 19 subjects diagnosed with schizophrenia (DSM-IV) and 19 matched controls were studied. In specific brain regions, levels of four endocannabinoids (2-arachidonoylglycerol (2-AG), arachidonoylethanolamine (anandamide, AEA), dihomo-gamma-linolenoylethanolamine (LEA), and docosahexaenoylethanolamine (DHEA)) and two cannabimimetic compounds (palmitoyl-ethanolamine (PEA) and oleoyl-ethanolamine (OEA)) were measured using quantitative liquid chromatography with triple quadrupole mass spectrometric detection. Suffering from schizophrenia significantly affects the brain levels of 2-AG (p<0.001), AEA (p<0.0001), DHEA (p<0.0001), LEA (p<0.01) and PEA (p<0.05). In schizophrenic subjects, the three studied brain regions (cerebellum: 130+/-18%; p=0.16; hippocampus: 168+/-28%, p<0.01; prefrontal cortex: 237+/-45%, p<0.05) showed higher 2-AG levels when compared to matched controls. Conversely, AEA levels were lower in all brain regions of schizophrenic subjects (cerebellum: 66+/-7%, p<0.01; hippocampus: 66+/-7%, p<0.01; prefrontal cortex: 75+/-10%, p=0.07). Statistically significant lower levels of DHEA were also found in cerebellum (60+/-6%, p<0.001) and hippocampus (68+/-7%, p<0.05) of schizophrenic subjects. PEA (71+/-6%, p<0.05) and LEA (72+/-6%, p<0.05) levels were also found to be lower in cerebellum. No significant differences were found in OEA levels. Our results evidence specific alterations in the levels of some endocannabinoids in different brain regions of schizophrenic subjects. Furthermore, these data evidence the involvement of the endocannabinoid system in the pathophysiology of schizophrenia.