The study aimed to evaluate the effects of midazolam and diphenhydramine for the prevention of metoclopramide-induced akathisia.This randomized, double-blind, and controlled trial aimed to investigate coadministered midazolam vs diphenhydramine in the prophylaxis of metoclopramide-induced akathisia. Patients 18 to 65 years of age who presented to the emergency department with primary or secondary complaints of nausea and/or moderate to severe vascular-type headache were eligible for this study. Patients were randomized to one of the fallowing 3 groups: (1) metoclopramide 10 mg + midazolam 1.5 mg; (2) metoclopramide 10 mg + diphenhydramine 20 mg; (3) metoclopramide 10 mg + placebo. Metoclopramide was administered as a 2-minute bolus infusion. Midazolam, diphenhydramine, and normal saline solution were administered as a 15-minute slow infusion. The whole procedure was observed; and akathisia and sedation scores and vital changes were recorded.There were significant differences among groups with respect to akathisia (P = .016) and sedation (P < .001). The midazolam group showed the lowest mean akathisia score but the highest mean sedation score. Akathisia scores of the diphenhydramine group were not different from placebo. There were significant differences among groups in terms of changes in mean vital findings such as respiration rates, pulse rates, and systolic blood pressures (P < .05). There were no significant difference among groups in terms of changes in mean diastolic blood pressures (P = .09).Coadministered midazolam reduced the incidence of akathisia induced by metoclopramide compared to placebo but increased the rate of sedation. No difference was detected from diphenhydramine. Routine coadministered 20 mg diphenhydramine did not prevent metoclopramide-induced akathisia.