Human papillomavirus has been shown to be associated with squamous carcinomas. We evaluated benign and malignant colon tissues for the presence of human papillomavirus infection to determine if a similar relationship exists between human papillomavirus and colon neoplasms. Colon tissues were screened using an immunohistochemical technique to detect human papillomavirus antigen. In situ DNA hybridization was then performed on those tissues that yielded positive results by immunohistochemistry. Groups were compared using chi 2 analysis. Human papillomavirus antigen was present in 23% of normal colon specimens, 60% of benign tumors, and 97% of carcinomas. Human papilloma viral genome was demonstrated in 27% of benign tumors and in nearly 43% of all carcinomas tested. These data indicate that human papillomavirus infects the columnar mucosa of the colon, and that an association exists between human papillomavirus and colon neoplasia.