Abstract Background Partial pressure of carbon dioxide (PaCO2) is generally known to influence outcome in patients with traumatic brain injury (TBI) at normal altitudes. Less is known about specific relationships of PaCO2 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 PaCO2 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 PaCO2 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 PaCO2 levels (OR 1.36, 95% CI 1.13–1.78, P = 0.015) remained significantly associated with the unfavorable outcome. Conclusions Higher PaCO2 levels are associated with an unfavorable outcome in ventilated patients with TBI. These results underscore the importance of PaCO2 levels in patients with TBI and whether it should be adjusted for populations living at higher altitudes.