Background Awareness is a serious complication of general anesthesia. In China, the incidence of intraoperative awareness was 1% in patients undergoing total intravenous anesthesia (TIVA). In this study, we compared the incidence of awareness between Bispectral index (BIS)-guided and routine TIVA protocol and evaluated the effect of BIS on preventing awareness. Methods A prospective, randomized, double-blinded, multicenter controlled trial was performed. Patients (>= 18 years of age) undergoing TIVA were randomly divided into BIS-guided group (Group A, BIS was monitored and recommended to maintain between 40-60) and control group (Group B, BIS was monitored but the screen was covered). The intraoperative BIS values were downloaded and the BIS trends of confirmed awareness cases were analyzed to determine whether light anesthesia existed. Results Of the total 5228 patients, 2919 patients were assigned to Group A and 2309 to Group B. Four cases of confirmed awareness (0.14%) were reported in the BIS-guided group and 15 (0.65%) in the control group (P=0.002, OR=0.21, 95% confidence intervals: 0.07-0.63). The incidence of possible awareness (0.14% vs. 0.26%, P=0.485) and dreaming (3.1% vs. 3.1%, P=0.986) was comparable between BIS-guided group and the control group. Among the 19 confirmed awareness cases, intraoperative BIS trends of six cases were downloaded and identified. Five of them showed signs of light anesthesia as BIS >60 and lasted 19-106 minutes, whereas one case had a stable BIS trend and the values were within 60 during the operation. Another five awareness cases were reviewed for anesthesia procedures, of which improper light anesthesia were confirmed. Conclusions BIS-guided TIVA (BIS was recommended to maintain between 40-60) decreased the risk of awareness compared with routine TIVA. The main reason for awareness was light anesthesia. Chin Med J 2011;124(22):3664-3669