Schizophrenia and obsessive-compulsive disorder (OCD) are complex neuropsychiatric disorders with emerging evidence implicating immune and neuroinflammatory mechanisms. This exploratory pilot study investigated aquaporin-4 positive (AQP4+) extracellular vesicles (EVs) in the cerebrospinal fluid (CSF) of 11 treatment-resistant patients with schizophrenia (n = 5) or obsessive-compulsive disorder (OCD, n = 6) receiving an add-on, single-infusion rituximab (1000 mg) treatment, a B-cell depleting therapy. CSF samples were collected pre-treatment and, for a subset, again five months post-treatment. AQP4+ EV levels in CSF were quantified using flow cytometry with antibodies targeting different regions of the AQP4 molecule. We also measured selected cytokines in CSF and plasma and cytokine gene expression in peripheral blood cells. Patients with schizophrenia exhibited higher AQP4+ EV levels compared to those with OCD. In schizophrenia, AQP4+ EVs correlated positively with the inflammatory marker CXCL8/IL-8 but negatively with CSF-TNF-α. Plasma markers CXCL8/IL-8 and TGF-β1 were positively associated with CSF-AQP4+ EVs in schizophrenia. Between 24- and 40-times higher concentrations of CXCL8/IL-8 in CSF than in plasma suggest intrathecal production of this chemokine in both disorders. Post-treatment, AQP4+ EV levels decreased in the patients who improved following rituximab but remained stable in non-responders. These findings suggest that astrocyte-derived extracellular vesicles may play a role in neuroinflammatory processes linked to schizophrenia and possibly also to severe OCD. The observed relationships between AQP4+ EVs and cytokines support the hypothesis that astrocyte-derived EVs could modulate intrathecal immune responses and potentially also interact with peripheral immune mechanisms. Larger studies are warranted to validate these preliminary findings.