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Objective To explore the clinical changes of peripheral inflammatory markers and oxidative stress during post-acute and chronic phase after severe traumatic brain injury (sTBI). Methods A total of 24 sTBI patients were included in this study. The changes of peripheral inflammatory markers [interleukin (IL)-1β, IL-6, interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α)] and oxidative parameters [glutathione peroxidase (GSH - Px), superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR) and total plasma antioxidant activity (TEAA)] were monitored. Functional Independence Measure (FIM) and Dyskinesia Rating Scale (DRS) were used to evaluate cognitive function and motor function. Results There were significant differences on IL-6 (F = 105.982, P = 0.000), IFN (F = 19.873, P = 0.000), GSH-Px (F = 162.090, P = 0.000), SOD (F = 28.254, P = 0.000) and CAT (F = 4.782, P = 0.011) during different periods of sTBI (post-acute phase, chronic early phase, chronic phase). IL-6 and GSH-Px in chronic early phase (IL-6: t = 11.753, P = 0.000; GSH-Px: t = 16.901, P = 0.000) and chronic phase (IL-6: t = 14.533, P = 0.000; GSH-Px: t = 13.828, P = 0.000) were significantly lower than post-acute phase. IL-6 and GSH-Px in chronic phase (IL-6: t = 2.341, P = 0.012; GSH-Px: t = 3.073, P = 0.003) were significantly lower than chronic early phase. SOD in chronic early phase and chronic phase was significantly higher than post - acute phase (t = 7.264, P = 0.000; t = 5.303, P = 0.000). CAT in chronic early phase was significantly higher than post-acute phase (t = 3.060, P = 0.003). After 12 months, 24 patients completed the follow-up, and their FIM scores were significantly increased (t = 36.260, P = 0.000), while DRS scores were significantly decreased (t = 49.010, P = 0.000). Pearson correlation analysis showed that IL-6 (r = 0.446, P = 0.020) and GSH-Px (r = 0.142, P = 0.000) were positively correlated with overall cognitive performance index (CPI). IL-6 was positively correlated with attention (r = 0.431, P = 0.026) and executive function (r = 0.522, P = 0.005) of synthetic index (SI). IFN-γ (r = 0.497, P = 0.009) and TNF-α (r = 0.479, P = 0.009) were positively correlated with executive function of SI. GSH-Px was positively correlated with all SI (r = 0.220, P = 0.000; r = 0.344, P = 0.000; r = 0.011, P = 0.000). Conclusions Imbalance of oxidative stress response and over-production of inflammatory markers in acute phase of patients with severe traumatic brain injury might adversely affect the neurological functional recovery. Inflammatory markers and oxidative stress response might offer a feasible way to monitor recovery and predict the prognosis after severe traumatic brain injury. [ABSTRACT FROM AUTHOR]