Background <p>Obese patients are at increased risk for oxygenation impairment during procedures such as esophagogastroduodenoscopy (EGD), with patient positioning playing a critical role. However, limited data exist comparing the safety and oxygenation effects of left lateral versus supine positioning in bariatric patients undergoing EGD.</p> Objectives <p>To evaluate the impact of supine versus left lateral decubitus positioning on safety and oxygenation status during EGD in patients with morbid obesity.</p> Setting <p>Tampa General Hospital, a university-affiliated academic medical center (University of South Florida Morsani College of Medicine), United States.</p> Methods <p>This retrospective cohort study analyzed adults (BMI ≥ 35) undergoing EGD from October 2020 to July 2023. Patients were grouped by position: left lateral (Group 1) and supine/semi-Fowler (Group 2). The primary outcome was unplanned intubation. Secondary outcomes included procedure time, maximum FiO₂, and post-operative oxygen saturation. Statistical significance was set at <i>P</i> &lt; 0.05.</p> Results <p>A total of 495 patients were included: 240 in Group 1 and 253 in Group 2. No significant difference in unplanned intubation was observed (0.4% in both groups; <i>P</i> = 0.970). Supine-positioned patients had shorter procedure times (14.35 vs. 16.40&#xa0;min; <i>P</i> &lt; 0.0001) but required higher maximum FiO₂ (84.98 vs. 78.08; <i>P</i> = 0.014). Post-operative oxygen saturations were similar between groups (<i>P</i> = 0.774).</p> Conclusions <p>Supine positioning during EGD in morbidly obese patients was not associated with an increased rate of unplanned intubation compared with left lateral positioning. Although supine positioning was associated with higher oxygen support requirements, it was also associated with shorter procedure times, suggesting it may be considered in appropriately selected patients when oxygenation needs are anticipated.</p>