Abstract： Objective:To explore the clinical efficacy and mechanism of hyperbaric oxygen（HBO）combined with high-dose dexamethasone in the treatment of late stage radiation encephalopathy（RE）after radiotherapy for nasopharyngeal carcinoma.Methods:A total of 108 patients with late stage RE after radiotherapy for nasopharyngeal carcinoma，who were admitted to the Department of Oncology at Yantai Penglai People’s Hospital from April 2015 to April 2023，were selected as the study subjects. The 108 patients were divided into combined treatment group（ n=54）and control group（ n=54）acording to the random number table method. The patients in the control group were treated with high-dose dexamethasone，while the petients in the combination group received HBO therapy on the basis of treatment in the control group. Cranial MRI scans were conducted to assess changes in the volume of intracranial lesions in patients before and after treatment for evaluating the clinical efficacy. The cognitive function and activities of daily living of patients before and after treatment were evaluated using the mini-mental state examination（MMSE）scale and the modified Barthel index（MBI），respectively. Changes in the scores of various factors related to quality of life before and after treatment were evaluated using the World Health Organization quality of life-bref（WHO QOL-bref）. Levels of serum Interleukin 6（IL-6），vascular endothelial growth factor（VEGF），hypoxia-inducible factor-1α（HIF-1α），and angiotensin converting enzyme（ACE）before and after treatment were measured by enzyme-linked immunosorbent assay（ELISA）. Results:The combined treatment group demonstrated significantly smaller volume of intracranial lesions compared with the control group after treatment（ P<0.05）. The total effective rate in the combined treatment group（87.04%）was significantly higher than that in the control group（74.07%）after treatment，with a statistically significant difference（ χ2=4.112， P=0.031）. Both the MMSE and MBI scores in the combined treatment group were significantly higher than those in the control group after treatment（ P<0.05）. After treatment，the combined treatment group exhibited significantly higher scores in the physiological，psychological，social environment relationships，overall health，and life domains compared with the control group（ P<0.05 or P<0.01）. Compared with those before treatment，the levels of serum VEGF and ACE in both groups significantly increased after treatment，while HIF-1α and IL-6 levels decreased significantly（ P<0.01）. Compared with those in the control group after treatment，the levels of serum ACE in the combined treatment group significantly increased，but the levels of HIF-1α and IL-6 significantly decreased（ P<0.05 or P<0.01）. Conclusion:HBO therapy combined with high-dose dexamethasone in the treatment of late stage RE after radiotherapy for nasopharyngeal carcinoma significantly improves clinical outcomes by reducing the volume of intracranial lesions，enhancing cognitive function，and activities of daily living. The main mechanism of action is achieved through upregulation of serum ACE expressions，along with inhibitions of VEGF，HIF-1α，and IL-6 release.