Background: Awareness with explicit recall of intra-operative events is a rare and distressing complication that may lead to severe psychological symptoms. Candidate depth of anesthesia monitors have been developed, partly with the aim of preventing this complication. Despite conflicting results from clinical trials and the lack of incisive validation, such monitors have enjoyed widespread clinical adoption, in particular the bispectral index. The American Society of Anesthesiologists has called for adequately powered and rigorously designed clinical trials to determine whether the use of such monitors decreases the incidence of awareness in various settings. The aim of this study is to determine with increased precision whether incorporating the bispectral index into a structured general anesthesia protocol decreases the incidence of awareness with explicit recall among a subset of surgical patients at increased risk for awareness and scheduled to receive an inhalation gas-based general anesthetic. Methods/Design: BAG-RECALL is a multi-center, randomized, controlled clinical trial, in which 6,000 patients are being assigned to bispectral index-guided anesthesia (target range, 40 to 60) or end-tidal anesthetic gas-guided anesthesia (target range, 0.7 to 1.3 age-adjusted minimum alveolar concentration). Postoperatively, patients are being assessed for explicit recall at two intervals (0 to 72 hours, and 30 days after extubation). The primary outcome of the trial is awareness with explicit recall. Secondary outcomes include postoperative mortality, psychological symptoms, intensive care and hospital length of stay, average anesthetic gas administration, postoperative pain and nausea and vomiting, duration of stay in the recovery area, intra-operative dreaming, and postoperative delirium. Discussion: This trial has been designed to complement two other clinical trials: B-Unaware and MACS (ClinicalTrials.gov numbers, NCT00281489 and NCT00689091). With the large patient numbers and complementary rigorous designs, it is envisaged that pre-specified meta-analyses will address some of the outstanding controversies and questions relating to processed electroencephalography monitoring. Trial registration: ClinicalTrials.gov Identifier: NCT00682825.