Objective: Pre-treatment with either fentanyl or midazolam has previously been used to prevent etomidate-induced myoclonus (EIM). The aim of the present study was to determine the effect of pre-treatment with a combination of midazolam and fentanyl in reducing the incidence and severity of EIM.Methods: This prospective, randomised, double-blind study was conducted on 210 surgical patients allocated to three study groups. Group F patients received fentanyl 2 μg kg−1 and 5 mL saline. Group M patients received midazolam 0.03 mg kg−1 and 5 mL saline. Group FM patients received fentanyl 2 μg kg−1 plus midazolam 0.03 mg kg−1. The study drugs were administered intravenously over 30 s. Five minutes after study drug administration, etomidate 0.3 mg kg−1 was administered over 60 s. Patients were observed for 1 min for occurrence and severity of EIM.Results: The incidence of EIM was 34/70 (48.6%), 55/70 (78.6%) and 11/70 (15.7%) in groups F, M and FM, respectively (p=0.001). Myoclonus of moderate or severe grade occurred in 23/70 (32.9%), 45/70 (64.3%) and 6/70 (8.6%) in groups F, M and FM, respectively (p=0.001). Patients who experienced myoclonus exhibited a significantly higher percentage change in post-induction heart rate (p=0.02), systolic blood pressure (p=0.001) and mean blood pressure (p=0.001) from pre-induction values than those who did not.Conclusion: Pre-treatment with a combination of fentanyl and midazolam is more effective than that with fentanyl or midazolam alone in reducing the incidence and severity of EIM. Myoclonus is associated with a higher post-induction haemodynamic variation.