<p>Cognitive impairment is a core feature of schizophrenia, yet the biological basis has not been established. Redox dysregulation has been implicated in cognitive impairment of patients with schizophrenia but evidence in early-stage, drug-naïve patients is limited and inconsistent. Herein we examined glutathione-related redox markers and the associations with cognition in 96 drug-naïve, first-episode schizophrenia patients and 94 matched controls. Patients with schizophrenia exhibited a systemic redox imbalance that was characterized by increased glutathione (GSH) and glutathione disulfide (GSSG) levels with a reduced GSH-to-GSSG ratio, while glutathione reductase activity remained unchanged. Marked cognitive deficits were observed across all domains. Among redox markers, GSSG showed robust and consistent negative associations with global cognition and multiple domains, and emerged as an independent predictor after covariate adjustment. In contrast, GSH and the GSH-to-GSSG ratio had weaker and less stable associations. No reliable relationships were demonstrated between redox markers and clinical symptoms after correction for multiple comparisons. These findings are the basis for a functionally asymmetric redox dysregulation model, in which increased oxidative load, indexed by GSSG, has a central role in early cognitive impairment, relatively independent of antioxidant capacity. These findings highlight GSSG as a candidate biomarker for early cognitive impairment and suggest redox-targeted interventions as a potential therapeutic strategy in schizophrenia.</p>