During normal keratinocyte differentiation, a coordinated expression of many cytoskeletal and regulatory proteins occurs. Several studies suggest that expression of some of these proteins is altered in epithelium infected by the human papillomavirus (HPV). To examine protein expression, human foreskin tissue was infected with either the low-risk HPV type 11 or with HPV 83, a high-risk type. The foreskin tissue was implanted and grown in the athymic mouse xenograft system. Immunohistochemistry and immunoblot analysis of human foreskin xenografts were performed to detect cytokeratin 16 (K16), a protein previously identified in proliferative disorders of the skin. K16 was abundant in HPV 11-infected xenograft tissue, but was not detected in uninfected or HPV 83-infected tissue. Analysis of protein extracted from human biopsy tissue demonstrated the same expression patterns in natural infection by HPV 11. Reverse transcriptase PCR detected mRNA transcripts for K16 in both experimental and natural HPV 11-infected tissues, but not in uninfected tissue. These studies suggest that K16 overexpression during HPV 11-infection is regulated at the level of transcription. The marked epithelial proliferation that occurs in HPV 11 infection may involve alterations in expression of cytoskeletal proteins, including K16. Determining the mechanisms of K16 transcriptional induction could lead to therapies with the ability to reduce cell proliferation within infected tissue.