Background: Pannexin-1 is a type of hexameric plasma membrane channel-forming proteins, and plays a significant role in brain injury. We investigated the potential prognostic value of pannexin-1 in traumatic brain injury. Methods: A single peripheral blood sample in 112 patients with severe traumatic brain injury and 112 controls was prospectively collected for subsequent measurement of serum pannexin-1. Clinical follow-up was performed at 6 months. An unfavorable outcome was defined as Glasgow Outcome Scale score of 1-3. Results: The patients showed markedly higher serum pannexin-1 concentrations than the controls. Among the patients, pannexin-1 concentrations were significantly and negatively correlated with Glasgow coma scale scores. On receiver operating characteristic curve analysis, the predictive value in terms of area under the curve was substantially high for serum pannexin-1 as a predictor for both 6-month mortality and unfavorable outcome. Regression analyses confirmed that there was an increased risk of either 6-month mortality, overall survival or unfavorable outcome associated with serum pannexin-1 concentrations after adjusting for possible confounders. Conclusions: Serum pannexin-1 may represent a potential prognostic biomarker for head trauma.