It is important for physicians in intensive care units to be able to predict the presence and severity of central nervous system injury in patients with severe head injury (SHI). The extent of S100B elevation has been found to be useful in predicting clinical outcome after brain injury. However, only two studies were realized with jugular venous blood samples. The purpose of our study is to compare the interest between jugular venous and arterial concentrations evaluation of serum S100B protein in patients with SHI. We recruited 17 patients with a SHI, admitted to the intensive care unit. Paired arterial and jugular venous samples were taken at kinetically after injury. S100B median was 0.16 μg/L in arterial and 0.25 μg/L in jugular. This arterio-jugular difference is significant. However, there was any significant arterio-jugular difference in the patients group showing an unfavourable outcome or for the earlier samples (earlier than 24h). We observed there was no significant decrease of S100B in jugular, unlike in arterial, 24h after the head injury in the patients group showing an unfavourable outcome. Determination of S100B concentration in jugular samples appears to be better than in arterial to predict clinical outcome after brain injury.