Background and Aims: Esophagogastroduodenoscopy (EGD) has been identified as an aerosol-generating procedure (AGP) during the COVID-19 pandemic. The risk of AGP and benefits of utilizing protective measures have never been fully studied. Methods: A randomized control, open-label study in patients scheduled for diagnostic EGD between September and December 2021 was conducted. Patients were randomly assigned to either head box group or without head box group (control group). Particles were measured with six-size particle counters at the nurse anesthetist and endoscopist position. Primary composite outcomes were the mean difference of aerosol particle levels during and before EGD at the nurse anesthetist face position and at the endoscopist face position. Secondary outcomes were factors increasing aerosol particle levels and safety of the head box. Results: From 196 enrolled patients, 190 were analyzed. Baseline characteristics were not different between the two groups. The mean distance between endoscopist face and patient mouth was 67.2 ± 4.9 cm. The mean differences of 0.3-, 0.5-, and 1.0-μm particles during the procedure and at baseline before the procedure at nurse anesthetist position and the mean differences of 0.3-μm particles at the endoscopist position was found to have decreased in the head box group and increased in the control group (P < 0.001, 0.001, 0.014, and P < 0.001, respectively). Cough, burping, and body movement increased aerosol particles. No additional adverse events were observed in the head box group. Conclusions: EGD with the head box is safe and can reduce significant aerosolization to endoscopy personnel including nurse anesthetists and endoscopists.