To investigate the reliability of unilateral jugular venous monitoring and to determine the appropriate side, we performed bilateral jugular venous monitoring in 22 head-injured patients. Fiberoptic catheters were placed in both jugular bulbs. Arterial and bilateral jugular venous blood samples were obtained simultaneously for in vitro determination of jugular venous oxygen saturation (SJO2), arterial minus jugular venous lactate content difference (AJDL), and modified lactate-oxygen index (mLOI). Ischemia was assumed if one of the following pathologic values occurred at least unilaterally: SJO2 <54%, AJDL <-0.37 mmol/L, mLOI >0.08. The sensitivity of calculated unilateral monitoring in detecting ischemia was evaluated by comparing the incidence detected unilaterally with that disclosed bilaterally. The mean and maximum bilateral SJO2 differences varied between 1.4% and 21.0%, and 8.1% and 44.3%, respectively. The bias and limits of agreement (mean differences +/- 2 SD) between paired samples were 0.4% +/- 12.8%. There was no significant variation in bilateral SJO2 differences with time. Decreasing cerebral perfusion pressure (r = -0.559, P < 0.001) and arterial PCO2 (r = -0.342, P < 0.001) were associated with increasing bilateral SJO2 differences. Regarding AJDL, the maximum bilateral differences varied between 0.04 mmol/L and 1.52 mmol/L. The bias and limits of agreement were -0.01 +/- 0.18 mmol/L. At best, 87% of ischemic events were disclosed by monitoring on the side of predominant lesion or, in diffuse injuries, on the side of the larger jugular foramen (computed tomographic [CT] approach). We conclude that in severe head injury, even calculated unilateral jugular venous monitoring has an unpredictable risk for misleading or missing data. Therefore, the reliability of unilateral jugular venous monitoring appears suspicious. For diagnosing ischemia the CT approach is recommended.