BACKGROUND: Same-day performance of esophagogastroduodenoscopy (EGD) and colonoscopy is called bidirectional endoscopy (BDE). BDE is commonly performed, but the optimal sequence for which procedure to do first is not well established. This is the first study in the US to investigate the optimal sequence for BDE. METHODS: We performed a cohort study of patients with same-day BDE (2003-2018) at our institution. The two study groups were (1) EGD followed by colonoscopy (UL) and (2) Colonoscopy followed by EGD (LU). Endpoints included procedure duration, extent reached, sedation, and diagnostic yield. RESULTS: 22,905 patients underwent BDE, with complete data available for 16,538. 14,325 underwent UL, and 2213 underwent LU. For diagnostic indications, the LU group was more likely to require opiates (OR 2.8, CI 2.5-3.3, p <
0.002), benzodiazepines (OR 3.0, CI 2.6-3.4, p <
0.002), antihistamines (OR 1.5, CI 1.2-1.8, p <
0.002), while less likely to require anesthesia (OR 0.33, CI 0.28-0.39, p <
0.002). Similar results were found for surveillance indication of endoscopy and in screening colonoscopy, with no differences in EGD screening indications. Total Procedure duration: UL had shorter total procedure duration (23.2 vs. 28.8 min
p <
0.002), EGD duration (5.4 vs. 6.5 min
p <
0.002), and colonoscopy duration (17.9 vs. 22.3 min
p <
0.002). Diagnostic yield: UL and LU sequences had comparable polyp detection rates (37.6% vs. 38.1%, p = 0.65) with similar adenoma detection rates (ADR). CONCLUSION: Performing EGD first resulted in shorter procedure times and a reduced likelihood of requiring opioids and benzodiazepines, with no differences regarding procedure-related adverse events or diagnostic yield.