Abstract Background Partial pressure of carbon dioxide (PaCO 2 ) is generally known to influence outcome in patients with traumatic brain injury (TBI) at normal altitudes. Less is known about specific relationships of PaCO 2 levels and clinical outcomes at high altitudes. Methods This is a prospective single-center cohort of consecutive patients with TBI admitted to a trauma center located at 2600 m above sea level. An unfavorable outcome was defined as a Glasgow Outcome Scale-Extended (GOSE) score < 4 at the 6-month follow-up. Results We had a total of 81 patients with complete data, 80% (65/81) were men, and the median (interquartile range) age was 36 (25–50) years. Median Glasgow Coma Scale (GCS) score on admission was 9 (6–14); 49% (40/81) of patients had severe TBI (GCS 3–8), 32% (26/81) had moderate TBI (GCS 12–9), and 18% (15/81) had mild TBI (GCS 13–15). The median (interquartile range) Abbreviated Injury Score of the head (AISh) was 3 (2–4). The frequency of an unfavorable outcome (GOSE < 4) was 30% (25/81), the median GOSE was 4 (2–5), and the median 6-month mortality rate was 24% (20/81). Comparison between patients with favorable and unfavorable outcomes revealed that those with unfavorable outcome were older, (median age 49 [30–72] vs. 29 [22–41] years, P < 0.01), had lower admission GCS scores (6 [4–8] vs. 13 [8–15], P < 0.01), had higher AISh scores (4 [4–4] vs. 3 [2–4], P < 0.01), had higher Acute Physiology and Chronic Health disease Classification System II scores (17 [15–23] vs. 10 [6–14], P < 0.01), had higher Charlson scores (0 [0–2] vs. 0 [0–0], P < 0.01), and had higher PaCO 2 levels (mean 35 ± 8 vs. 32 ± 6 mm Hg, P < 0.01). In a multivariate analysis, age (odds ratio [OR] 1.14, 95% confidence interval [CI] 1.1–1.30, P < 0.01), AISh (OR 4.7, 95% CI 1.55–21.0, P < 0.05), and PaCO 2 levels (OR 1.23, 95% CI 1.10–1.53, P < 0.05) were significantly associated with the unfavorable outcomes. When applying the same analysis to the subgroup on mechanical ventilation, AISh (OR 5.4, 95% CI 1.61–28.5, P = 0.017) and PaCO 2 levels (OR 1.36, 95% CI 1.13–1.78, P = 0.015) remained significantly associated with the unfavorable outcome. Conclusions Higher PaCO 2 levels are associated with an unfavorable outcome in ventilated patients with TBI. These results underscore the importance of PaCO 2 levels in patients with TBI and whether it should be adjusted for populations living at higher altitudes.