The presence of human papilloma virus (HPV) has recently been demonstrated in colon tumors, but the incidence of HPV infection in normal colon mucosa or in benign or malignant neoplasms of the mucosa is unknown. We studied both neoplastic and normal human colon tissue for the presence of HPV antigen using immunohistochemical techniques. Ninety colon specimens were studied. Three consecutive series of normal colon mucosa (N = 30), single benign tubulovillous adenomas (N = 30), and invasive carcinomas (N = 30) were selected and confirmed histologically. Formalin-fixed paraffin-embedded samples of each tissue were prepared using immunohistochemical techniques and resultant slides were read blindly and graded simply as positive or negative for HPV antigen. The presence of HPV antigen varied dramatically between groups, with 97% of the invasive carcinomas, 60% of the benign tubulovillous adenomas, and 23% of the normal mucosa positive for HPV antigen. Groups were statistically significant using chi 2 analysis (P less than 0.001). We conclude that an association exists between the human colon neoplasia and the presence of HPV antigen. This may suggest an etiologic role of the virus in colon cancer.