AIM: To investigate two distinct clinical phenotypes of reflux esophagitis and intra-hernial ulcer (Cameron lesions) in patients with large hiatal hernias. METHODS: A case series study was performed with 16 831 patients who underwent diagnostic esophagogastroduodenoscopy for 2 years at an academic referral center. A hiatus diameter ≥ 4 cm was defined as a large hernia. A sharp fold that surrounded the cardia was designated as an intact gastroesophageal flap valve (GEFV), and a loose fold or disappearance of the fold was classified as an impaired GEFV. We studied the associations between large hiatal hernias and the distinct clinical phenotypes (reflux esophagitis and Cameron lesions), and analyzed factors that distinguished the clinical phenotypes. RESULTS: Large hiatal hernias were found in 49 (0.3%) of 16 831 patients. Cameron lesions and reflux esopha-gitis were observed in 10% and 47% of these patients, and 0% and 8% of the patients without large hiatal hernias, which indicated significant associations between large hiatal hernias and these diseases. However, there was no coincidence of the two distinct disorders. Univariate analysis demonstrated significant associations between Cameron lesions and the clinico-endoscopic factors such as nonsteroidal anti-inflammatory drug (NSAID) intake (80% in Cameron lesion cases vs 18% in non-Cameron lesion cases, P=0.015) and intact GEFV (100% in Cameron lesion cases vs 18% in non-Cameron lesion cases, P=0.0007). In contrast, reflux esophagitis was linked with impaired GEFV (44% in reflux esophagitis cases vs 8% in non-reflux esophagitis cases, P = 0.01). Multivariate regression analysis confirmed these significant associations. CONCLUSION: GEFV status and NSAID intake distinguish clinical phenotypes of large hiatal hernias. Cameron lesions are associated with intact GEFV and NSAID intake. A investigate two distinct clinical phenotypes of reflux esophagitis and intra-hernial ulcer (Cameron lesions) in patients with large hiatal hernias. METHODS: A case series study was performed with 16 831 patients who underwent diagnostic esophagogastroduodenoscopy for 2 years at an academic referral A sharp fold that surrounded the cardia was designated as an intact gastroesophageal flap valve (GEFV), and a loose fold or disappearance of the fold was classified as an impaired GEFV. We studied the associations between large hiatal hernias and the distinct clinical phenotypes (reflux esophagitis and Cameron lesions), and analyzed factors that distinguished the clinical phenotypes. RESULTS: Large hiatal hernias were found in 49 (0.3%) of 16 831 patients. and reflux esopha-gitis were observed in 10% and 47% of these patients, and 0% and 8% of the patients without large hiatal hernias, which indicated s However, there was no coincidence of the two distinct disorders. Univariate analysis is evidence of significant associations between Cameron lesions and the clinico-endoscopic factors such as nonsteroidal anti-inflammatory drug (NSAID) intake (80% in Cameron lesion cases vs 18% in non-Cameron lesion cases, P = 0.015) and intact GEFV (100% in Cameron lesion cases vs 18% in non-Cameron lesion cases, P = 0.0007) with impaired GEFV (44% in reflux esophagitis cases vs 8% in non-reflux esophagitis cases, P = 0.01). Multivariate regression analysis confirmed these significant associations. CONCLUSION: GEFV status and NSAID intake differentiation clinical phenotypes of large hiatal hernias. are associated with intact GEFV and NSAID intake.