BACKGROUND: Hypnotic depth during anesthesia affects electroencephalography waveforms and electroencephalogram-derived indices, such as the bispectral index (BIS). Titrating anesthetic administration against the BIS assumes reliable relationships between BIS values, electroencephalogram waveforms, and effect site concentration, beyond loss of responsiveness. Associations among BIS, end-tidal anesthetic concentrations (ETAC), and patient characteristics were examined during anesthetic maintenance, using B-Unaware trial data. METHODS: Pharmacokinetically stable ETAC epochs during intraoperative anesthetic maintenance were analyzed. A generalized estimating equation determined independent relationships among BIS, ETAC (in age-adjusted minimum alveolar concentration equivalents), patient characteristics, and 1-yr mortality. Further individual and population characteristics were explored graphically. RESULTS: A total of 3,347,523 data points from 1,100 patients were analyzed over an ETAC range from 0.42 to 1.51 age-adjusted minimum alveolar concentration. A generalized estimating equation yielded a best predictive equation: BIS = 62.9-1.6 (if age younger than 60 yr) -1.6 (if female) -2.5 (if American Society of Anesthesiologists physical status more than 3) -2.6 (if deceased at 1 yr) -2.5 (if N2O was not used) -1.4 (if midazolam dose more than 2 mg) -1.3 (if opioid dose more than 50 morphine equivalents) -15.4 × age-adjusted minimum alveolar concentration. Although a population relationship between ETAC and BIS was apparent, interindividual variability in the strength and reliability of this relationship was large. Decreases in BIS with increasing ETAC were not reliably observed. Individual-patient linear regression yielded a median slope of -8 BIS/1 age-adjusted minimum alveolar concentration (interquartile range -30, 0) and a median correlation coefficient of -0.16 (interquartile range -0.031, -0.50). CONCLUSIONS: Independent of pharmacokinetic confounding, BIS frequently correlates poorly with ETAC, is often insensitive to clinically significant changes in ETAC, and is vulnerable to interindividual variability. BIS is therefore incapable of finely guiding volatile anesthetic titration during anesthetic maintenance.