Histologic changes suggesting HPV infection are occasionally found adjacent to squamous cell carcinoma or in squamous papilloma of the esophagus, but the relationship between HPV infection and benign and malignant squamous lesions of the esophagus is not yet dear. The aim of this study was to examine the role of HPV in squamous lesions of the esophagus. Microscopic examination with emphasis on HPV infection was done on 15 cases of squamous cell carcinoma and 26 cases of squamous papilloma. In situ hybridization technique for wide-spectrum HPV probe was performed on 35 endoscopically biopsied esophageal tissues. Among the histologic parameters suggesting HPV infection, acanthosis was the most frequent finding: 100.0% in benign and malignant esophageal lesions, and koilocytosis and intraepithelial capillary loops were the second (92.7%).: Dyskeratosis, basal cell hyperplasia and bi- or multinucleation were 52.3%, 44.0% and 34.1% in frequency, respectively. On in situ hybridization study, the HPV DNA expression rates of 10 squamous cell carcinomas with evidence of HPV infection and 15 carcinomas without evidence of HPV infection were 60.0% and 33.3%, respectively. In contrast to the carcinoma cases, only one (10.0%) of 10 squamous papillomas revealed positive signal. In conclusion, HPV infection is strongly associated with squamous cell carcinoma, but the causal relation of HPV to squamous papilloma is inconspicous.