Arterio-venous pCO2 difference (AVDpCO2) and estimated respiratory quotient, the ratio between AVDpCO2 and arterio-venous O2 difference, may be potentially useful estimators of irreversible posttraumatic global cerebral ischemia. Our aim was to evaluate their relevance, along with arterio-venous lactate difference (AVDL) and lactate oxygen index (LOI), in early outcome prediction. The retrospective study involved 55 patients with severe head injury, admitted consecutively in a multidisciplinary intensive care unit of a general hospital. A retrograde jugular catheter was placed as soon as possible, allowing for 324 simultaneous arterio-jugular samples to be taken throughout the first 48-hour postinjury. Early brain death (within 48 h) was assumed to be due to early global ischemia. A multivariate model including clinical and radiologic descriptors and jugular bulb variables showed that a widening of AVDL and LOI was associated with early brain death. Whereas in the patients who died, a progressive worsening of AVDpCO2 and estimated respiratory quotient, associated with corresponding changes in AVDL and LOI were observed, in patients who survived the widening of AVDpCO2 normalized along with that of arterio-venous O2 difference. These findings suggest that the isolated measurement of widening AVDpCO2 is not specific for global cerebral ischemia, but its observation over time could be potentially more useful.