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Objectives To predict the outcome of patients with traumatic brain injury (TBI) using the optic nerve sheath diameter (ONSD) and the central venous minus arterial CO 2 pressure to arterial minus central venous O2 content ratio (Pcv-aCO2/Ca-cvO2) in prehospital settings.Design A prospective cohort study was conducted in China.Participants The study was conducted from October 2023 to October 2024, enrolling patients diagnosed with TBI. Participants presenting a Glasgow Coma Scale (GCS) <8 at initial assessment were included in the research. Patients were classified into four groups according to ONSD and Pcv-aCO 2/Ca-cvO2: Group A Pcv-aCO2/Ca-cvO2 >1.8 mm Hg/mL and ONSD >5.6 mm; Group B: Pcv-aCO2/Ca-cvO2 >1.8 mm Hg/mL and ONSD ≤5.6 mm; Group C: Pcv-aCO2/Ca-cvO2 ≤1.8 mm Hg/mL and ONSD >5.6 mm; and Group D: Pcv-aCO2/Ca-cvO2 ≤1.8 mm Hg/mL and ONSD ≤5.6 mm.Primary and secondary outcome measures 30-day mortality, functional neurological recovery at discharge (measured by Glasgow Outcome Scale (GOS)), and length of intensive care unit (ICU) stay were compared between the 4 groups.Results Our findings show that Group D had the lowest 30-day mortality, the shortest ICU stay and the highest good recovery at discharge (GOS score) among the four groups. Survival curves illustrated a decrease in 30-day mortality in group C patients after mannitol administration compared with patients who did not receive mannitol administration. The area under the receiver operating characteristic curve for Pcv-aCO 2/Ca-cvO2 combined with ONSD (0.907 (95% CI 0.843 to 0.941)) was higher than those for ONSD (0.851 (95% CI 0.791 to 0.911)) alone, Pcv-aCO2/Ca-cvO2 (0.814 (95% CI 0.744 to 0.873)) alone or initial GCS (0.823 (95% CI 0.763 to 0.889)). Calibration plots demonstrated a strong alignment between observed and predicted probabilities for ONSD, Pcv-aCO2/Ca-cvO2, the combination of ONSD and Pcv-aCO₂/Ca-cvO₂, and initial GCS.Conclusions ONSD combined with Pcv-aCO 2/Ca-cvO2 is a relatively novel method for predicting the outcome in TBI patients, especially in a prehospital setting. This dual approach may improve the prediction of early prognosis and guide osmotherapy treatment in patients with TBI.