Delayed neurological sequelae after carbon monoxide poisoning (DNS) is the most common neuropsychiatric sequelae of acute carbon monoxide (CO) poisoning. At present, there is no effective method to prevent or treat DNS. This study was performed to evaluate the efficacy of the combined application of dexamethasone, mannitol and hyperbaric oxygen (HBO2) in the treatment of patients with DNS. Methods: A total of 312 patients with DNS were recruited and randomly assigned into the experimental group

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... (10 mg/day dexamethasone, 100 ml/12 h mannitol + HBO2 therapy) and the control group (HBO2 only). All patients received conventional treatment. We used the Mini-Mental State Examination (MMSE) scale to assess the cognitive function, the remission rate (RR) to assess the clinical efficacy and the National Institutes of Health Stroke Scale (NIHSS) to assess the neurological function. In addition, we measured myelin basic protein (MBP) levels in the cerebrospinal fluid (CSF) to assess the extent of nerve damage. Results: Compared with the control group, the experimental group had significantly increased average MMSE score (P = 0.035) and RR (P = 0.021), significantly reduced average NIHSS score (P = 0.028) and significantly lower MBP level in CSF (P = 0.0019) after 4 weeks of treatment. Furthermore, compared with patients who received dexamethasone alone, patients who received dexamethasone and mannitol had higher average MMSE score (P = 0.012) and RR (P = 0.038) and lower average NIHSS score (P = 0.022) and MBP level in CSF (P = 0.002). Dexamethasone and mannitol combined with HBO2 did not significantly increase adverse effects. Conclusion: The combination therapy of dexamethasone–mannitol–HBO2 is better in treating DNS than HBO2 alone and HBO2 combination with dexamethasone, and it can be used as a potential new therapy in the future.