BACKGROUND: We have sought to develop methodology for deriving optimal bispectral index (BIS) values (BISopt) for patients with moderate/severe traumatic brain injury, using continuous monitoring of cerebrovascular reactivity and bispectral electroencephalography. METHODS: Arterial blood pressure, intracranial pressure, and BIS (a bilateral measure that is associated with sedation state) were continuously recorded. The pressure reactivity index, optimal cerebral perfusion pressure (CPPopt), and BISopt were calculated. Using BIS values and the pressure reactivity index, a curve fitting method was applied to determine the minimum value for the pressure reactivity index thus giving the BISopt. RESULTS AND CONCLUSIONS: Identification of BISopt was possible in all of the patients, with both visual inspection of data and using our method of BISopt determination, demonstrating a similarity of median values of 44.62 (35.03-59.98) versus 48 (39.75-57.50) (p = 0.1949). Furthermore, our method outperformed common CPPopt curve fitting methods applied to BISopt with improved percent (%) yields on both the left side 52.1% (36.3-72.4%) versus 31.2% (23.0-48.9%) (p < 0.0001) and the right side 54.1% (35.95-75.9%) versus 33.5% (12.5-47.9%) (p < 0.0001). The BIS values and BISopt were compared with cerebral perfusion pressure, mean arterial pressure, and CPPopt. The results indicated that BISopt's impact on pressure reactivity was distinct from CPPopt, cerebral perfusion pressure, or mean arterial pressure. Real-time BISopt can be derived from continuous physiologic monitoring of patients with moderate/severe traumatic brain injury. This BISopt value appears to be unassociated with arterial blood pressure or CPPopt, supporting its role as a novel physiologic metric for evaluating cerebral autoregulation. BISopt management to optimize cerebrovascular pressure reactivity should be the subject of future studies in moderate/severe traumatic brain injury.