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To assess prospectively the bleeding risk attributable to gastroduodenal biopsy in subjects taking antiplatelet medications.No prospective data exist regarding the bleeding risk attributable to endoscopic biopsy in patients taking antiplatelet agents. A majority of Western endoscopists withdraw antiplatelet agents before upper endoscopy, despite expert guidelines to the contrary.We performed a prospective, single-blind, randomized study in healthy volunteers participating in a larger study regarding the effect of antiplatelet agents on gastroduodenal mucosal healing. Multiple gastroduodenal biopsies were performed during 2 esophagogastroduodenoscopy in subjects dosed with aspirin enteric-coated 81 mg once daily or clopidogrel 75 mg once daily. Data for endoscopic bleeding, clinical bleeding, blood vessel size, and depth of biopsy in histology specimens were collected.Four hundred and five antral biopsies and 225 duodenal biopsies were performed during 90 esophagogastroduodenoscopy in 45 subjects receiving aspirin or clopidogrel. Median maximum blood vessel diameter per biopsy was 31.9 μ (range: 9.2 to 133.8). About 50.8% of biopsy specimens breached the muscularis mucosa. In the clopidogrel group, no bleeding events were noted after 350 biopsies [upper confidence limit (UCL) for probability of bleeding=0.0085]. In the aspirin group, there were no clinical events (UCL=0.0106) and one minor endoscopic bleeding event (UCL=0.0169).Consistent with expert guidelines, the absolute risk attributable to gastroduodenal biopsy in adults taking antiplatelet agents seems to be low. Half of routine biopsies enter submucosa. The largest blood vessels avulsed during biopsy correspond to midsized and large arterioles and venules.