Acute esophageal mucosal lesion (AEML) is a comprehensive disease that includes necrotizing esophagitis and acute erosive esophagitis, which result in upper gastrointestinal bleeding. However, little is known about AEML. We examined the clinicopathological features of 57 AEML cases. AEML presented as acute diffuse esophagitis showing an endoscopically erosive mucosa. The disease did not include corrosive injury, radiation-induced damage, infectious esophagitis, or acute exacerbation of chronic gastroesophageal reflux disease. AEML predominantly affected elderly men, and upper gastrointestinal bleeding was the frequent presenting symptom. Severe underlying diseases such as cranial nerve disease or pneumonia were observed in 98% of the patients. Esophageal sliding hernia and gastroduodenal ulcers were endoscopically observed in 67% and 63% of the patients, respectively. Deaths due to exacerbation of the underlying diseases accounted for 16%. Most cases rapidly improved with conservative management using a proton pump inhibitor or an H2 blocker. Therefore, AEML should be considered a disease having characteristics different from those of common gastroesophageal reflux disease.