"Sloughing esophagitis" (SE) is characterized by a 2-toned squamous epithelium with superficial necrotic keratinocytes overlying viable epithelium. We compared histologic and clinical findings to determine how cases clinically diagnosed as SE differed from cases with histologic sloughing but a different clinical diagnosis. In addition, we compared cases with inflammatory and noninflammatory histology. We searched departmental archives for esophageal biopsies with histologic sloughing features. We compared clinical and histologic findings for cases with and without clinical confirmation of SE and with and without histologic inflammation. We identified 52 patients, of whom 10 (19%) had clinically diagnosed SE, 18 (35%) had another diagnosis, and 24 (46%) had an unclear diagnosis. Endoscopic sloughing tended to be reported more often in cases with SE (P = .07). Histologic features did not discriminate between SE and other etiologies. Esophagitis resolved in 18 of 31 patients with follow-up, with no difference between sloughing and nonsloughing cases (P = .26). There were no clinical differences based on inflammatory and noninflammatory histology. SE has a classic microscopic appearance, but its findings are not specific, although endoscopic sloughing helps correlate histologic and clinical findings. In cases with histologic sloughing, pathologists should raise a broad differential diagnosis.