The pathogenesis of esophageal squamous papilloma is not known, but chronic mucosal irritation and infection with human papillomavirus are two proposed etiologies. To investigate these hypotheses, we analyzed the clinical data and histological features of 38 esophageal squamous papillomas from 33 patients and performed the polymerase chain reaction technique for detection of several common human papilloma virus types on a subset of cases (n = 26) with sufficient available material. Clinically, males were affected more often than females (M:F ratio = 24:9); average age was 50 (range, 2-86 years). Most papillomas occurred singly (85%) and were located in the distal esophagus (70%). Patients with esophageal squamous papillomas, especially those with lesions in the distal esophagus, commonly had an associated chronic and often severe form of esophageal mucosal irritation such as esophagitis or Barrett's esophagus. Esophageal squamous papillomas were small polyps (average size, 0.5 cm) that we classified histologically into three types (exophytic, 50%; endophytic, 37%; spiked, 13%) based on the predominant shape of the squamous papillae. Fifty percent of the papillomas (13 of 26) tested, from 57% of patients (12 of 21), were positive for human papilloma virus, most commonly type 16 (nine of 13), less often type 16 and 18 together (3/13), and rarely type 6b/11 (1 of 13). We propose a multifactorial etiology in which the synergistic action of mucosal irritation and human papilloma virus may be necessary for the development of esophageal squamous papillomas.