Background & Objective: Etomidate is commonly used in anesthesia practice because of its rapid recovery time, low incidence of apnea, and lower incidence of allergic reactions; but pain upon injection is one of the unfavorable complications of this drug, which can cause both physical and mental discomfort to the patients. It is imperative to use appropriate means to lower the pain at the injection site of etomidate in patients undergoing anesthesia. We conducted this study to compare the effects of lidocaine, lidocaine and the Valsalva maneuver, with a combination of lidocaine, melatonin and the Valsalva maneuver on decreasing the pain of etomidate injection. Methodology: This clinical trial enrolled 135 patients. The patients were allocated into 3 groups, with one group receiving lidocaine (Group 1), the second group receiving lidocaine and the Valsalva maneuver (Group 2), and the last group receiving a combination of lidocaine, melatonin and the Valsalva maneuver. The pain resulting from injecting etomidate was evaluated based upon the Visual Analog Scale (VAS) score (with 1 being no pain and 10 the most severe imaginable pain). Data were compared and analyzed using proper statistical tests using SPSS version 23. Results: The results of this study showed that the overall pain score in all of the groups after injection of etomidate did not show any significant difference. The mean VAS score in Group 1 was 0.27 ± 0.88, in Group 2 it was 0.16 ± 0.63, and in Group 3 0.04 ± 0.2. However, the difference between the groups was statistically not significant (P = 0.32). Conclusion: The current study shows that the pain on injection of etomidate in the three groups of the study was reduced in a similar fashion; however, in the group which combined lidocaine, melatonin and the Valsalva maneuver, pain was the lowest, but the overall differences in score in the three groups were statistically not different. Keywords: Etomidate, lidocaine, melatonin, Valsalva maneuver. Citation: Nazemroaya B, Poudeh ND. Comparison of the effect of lidocaine and its combination with melatonin and the Valsalva maneuver on etomidate induced injection pain. Anaesth. pain intensive care 2024;28(5):842−849; DOI: 10.35975/apic.v28i5.2279 Received: July 27, 2024; Reviewed: September 04, 2024; Accepted: September 09, 2024