Squamous cell papilloma of the esophagus has been regarded as a distinct rarity. After having reviewed the files of the Gastrointestinal Endoscopy Unit of our hospital we found 14 patients diagnosed as having an esophageal papilloma on endoscopy of about 18,000 patients during the period 1985-90. On histologic examination of the biopsy specimens 12 cases showed histologic characteristics typical of a squamous cell papilloma (SQP), 1 was a fibroid polyp, and another showed epithelial dysplasia without the features typical of SQP. To assess the role of human papillomavirus (HPV) recently implicated in the etiology of this tumor, we analyzed all specimens for the presence of HPV types 6, 11, 16, and 18 DNA by in situ DNA hybridization (ISH) and polymerase chain reaction (PCR). No viral DNA was found by either ISH or PCR in any of these lesions. The significance of these findings is discussed in relation to the previous evidence presented on HPV involvement in the development of esophageal squamous cell papillomas and in esophageal carcinogenesis.