Updated project metadata. Extracellular vesicles (EVs) are tiny membranous structures capable of mediating intercellular communication. In the brain, the role(s) of EVs have been extensively studied in the context of neurological diseases, but their potential implications in the neuropathology underlying human mental disorders remain largely unexplored. Here, we investigated the potential role(s) of brain EVs in schizophrenia (SZ) by analyzing these vesicles from the three post-mortem anatomical brain regions: prefrontal cortex (PFC), hippocampus (HC) and caudate (CAU), using next-generation discovery-driven proteomics. Our results indicate that EVs from SZ-affected brains present region-specific proteins associated with abnormal GABAergic and glutamatergic transmission, as well as alterations in proteins involved in synaptic decay, abnormal brain immunity, neuronal structural imbalances and impaired cell homeostasis. Our findings also provide the first evidence that molecular exchange networks are potentially active and mediated by EVs in cognitively healthy brains. These EV-mediated networks were partially reversed and largely disrupted in brains affected by SZ.