Esophageal mucosal biopsy specimens frequently show numerous distended squamous cells with pale cytoplasm, which we term "balloon cells." These cells often occur in clusters, have a patchy distribution, and predominate in the prickle-cell layer in biopsies from patients with gastroesophageal reflux. We studied the immunohistochemical characteristics of balloon cells and their associated clinical findings. We demonstrated by immunoperoxidase technique that balloon cells contain intracytoplasmic albumin and immunoglobulin light chains and show reduced staining for keratin, suggesting cellular injury with resultant uptake of plasma proteins and fluid. Balloon cells were absent or sparse in esophageal mucosal biopsy specimens from 12 normal control persons, but were observed in 7 of 10 patients (70%) with gastroesophageal reflux confirmed by pH-probe test (P = 0.001 versus normal controls), in 16 of 25 patients (64%) with clinically suspected reflux (P less than 0.001), and in 4 of 5 patients with infectious or chemotherapy-associated esophagitis. However, no consistent association was found between balloon cells and the presence of the usual histopathologic criteria for epithelial injury, such as increased height of vascular tufts or width of basal zone. We conclude that balloon cells are most commonly observed in biopsy specimens from patients with various causes of esophageal injury. We propose that balloon cells may be a marker for epithelial injury, possibly even when other histopathologic criteria for injury are absent.