Increasing evidence supports the association of squamous cell carcinoma of the finger and nail bed with human papillomavirus infection. We treated 12 patients with squamous cell carcinoma of the finger and nail bed, none of whom was originally diagnosed as having a malignant lesion. Half of the patients were referred for carbon dioxide laser ablation of what was believed to be a recalcitrant verruca vulgaris. Our objective was to evaluate these lesions for the presence of human papillomavirus by in situ hybridization techniques and the polymerase chain reaction. This is the first report of use of the polymerase chain reaction to detect human papillomavirus in formalin-fixed, paraffin-embedded specimens of periungual squamous cell carcinoma. Seven of the 12 lesions were evaluated for the presence of human papillomavirus by both in situ hybridization and the polymerase chain reaction. Five of the seven periungual lesions were found to contain human papillomavirus type 16 but not type 18 DNA with use of the polymerase chain reaction technique. In situ hybridization failed to identify human papillomavirus in any of these patients' tumors. Our data confirm the association between human papillomavirus and squamous cell carcinoma of the periungual region and suggest that biopsies should be performed on chronic, isolated lesions of the finger in adults before therapy is initiated.