A 47-year-old man with a history of a benign papilloma of the tongue 5 years earlier was treated for a squamous cell carcinoma of the tongue with surgical resection. An analysis of the tumor DNA using several methods showed the presence of human papillomavirus (HPV) type 11 sequences that migrated with the high molecular weight cellular DNA, suggesting integration of viral DNA into the cellular genome. A segment of the HPV DNA was cloned from the lesion and shown to be similar to prototype HPV 11 DNA, except for some variability in the viral long control region. The proviral DNA contained part of the L1 region, all of the viral long control region, the entire E6 and E7 open-reading frames, and at least a portion of the E1 region; the E4 region appeared to be deleted. The integration sites of the HPV DNA could not be specifically identified. An analysis of the p53 tumor suppressor gene region of the tumor DNA showed no evidence of mutation. These results suggest that the HPV 11 DNA may have had a role in the origin of the cancer in this patient.