BACKGROUND: Benzodiazepines have a hypnotic/sedative effect through the inhibitory action of gamma-aminobutyric acid type A receptor. Flumazenil antagonizes these effects via competitive inhibition, so it has been used to reverse the effect of benzodiazepines. Recently, flumazenil has been reported to expedite recovery from propofol/remifentanil and sevoflurane/remifentanil anesthesia without benzodiazepines. Endogenous benzodiazepine ligands (endozepines) were isolated in several tissues of individuals who had not received benzodiazepines. METHODS: Forty-five healthy unpremedicated patients were randomly allocated to either flumazenil or a control groups. Each patient received either a single dose of 0.3 mg of flumazenil (n = 24) or placebo (n = 21). After drug administration, various recovery parameters and bispectral index (BIS) values in the flumazenil and control groups were compared. RESULTS: Mean time to spontaneous respiration, eye opening on verbal command, hand squeezing on verbal command, extubation and time to date of birth recollection were significantly shorter in the flumazenil group than in the control group (P = 0.004, 0.007, 0.005, 0.042, and 0.016, respectively). The BIS value was significantly higher in flumazenil group than in the control group beginning 6 min after flumazenil administration. CONCLUSIONS: Administration of a single dose of 0.3 mg of flumazenil to healthy, unpremedicated patients at the end of sevoflurane/fentanyl anesthesia without benzodiazepines resulted in earlier emergence from anesthesia and an increase in the BIS value. This may indicate that flumazenil could have an antagonistic effect on sevoflurane or an analeptic effect through endozepine-dependent mechanisms.