OBJECTIVE Diagnostic esophagogastroduodenoscopy (EGD) is uncomfortable for most patients. We determined the efficacy of alprazolam, administered orally or sublingually, as premedication for sedation during EGD. METHODS Adult EGD candidates were randomly allocated to four groups (n = 55, each group) and received alprazolam (0.5 mg) sublingually or orally, placebo sublingually or orally at 30 minutes before EGD. Main outcome measures included procedure-related anxiety and pain/discomfort (assessed using 11-point numeric scales), patient overall tolerance (assessed using a 4-point Likert scale), need for intravenous sedation, and willingness to repeat the EGD if necessary. RESULTS Patients experienced greater reduction in anxiety score after medication with sublingual alprazolam (mean 2.25, standard deviation [SD] 1.73) compared with sublingual placebo (mean 0.10, standard error [SE] 0.15]; P < 0.001) and oral alprazolam (0.63, SE 0.14; P < 0.001). Also, pain/discomfort scores were lower with sublingual alprazolam compared with sublingual placebo (3.29, SE 0.29 vs. 4.16, SD 1.86; P = 0.024), and with oral alprazolam compared with oral placebo (3.48, SD 1.69 vs. 5.13, SD 2.39; P  < 0.001). Patient overall tolerance was better with sublingual alprazolam than with sublingual placebo (P = 0.005) or with oral alprazolam (P = 0.009). Regarding intravenous sedation, there was no difference between sublingual alprazolam and sublingual placebo (10.9 % vs. 10.9 %; P = 0.619) or between oral alprazolam and oral placebo (9.0 % vs. 12.7 %; P = 0.381). Willingness to repeat the procedure was greater with sublingual alprazolam than with sublingual placebo (50.9 % vs. 30.9 %; P = 0.026). CONCLUSIONS Sublingual alprazolam is an effective premedication for sedation during EGD. It reduces anxiety and pain/discomfort related to EGD and increases patient tolerance and willingness to repeat the EGD if necessary. BACKGROUND NCT01949038 ClinicalTrials.gov.