The role of human papillomavirus (HPV) infections in the development of verrucous carcinoma, a well-differentiated variant of squamous cell carcinoma with difficult differential diagnosis, is controversial in the literature. In this study, we analysed verrucous carcinoma from different origins for the presence and activity of a broad spectrum of HPV types, and carefully reviewed the histopathological features. A random series of 27 formalin-fixed, paraffin-embedded specimens of verrucous carcinoma was taken, representing the head and neck region (n=6), anogenital area (n=16) and extragenital skin region (n=5). After review of the histological slides, all samples were subjected to different polymerase chain reaction-based HPV detection techniques, together detecting a total of 83 HPV types, including both mucosal and cutaneous types. Histological revision was carefully performed. Lesions with keratinised papillae, blunt stromal invaginations and minimal cytological atypia were considered verrucous carcinoma. Condylomatous lesions with viral changes were defined as giant condyloma. Verrucous lesions that did not meet those criteria were classified as verrucous hyperplasia. Tumours with stromal infiltration were considered as invasive squamous cell carcinoma. Histological revision revealed that 13 out of 27 cases were verrucous carcinoma (one showing a double infection with HPV 35 and 45), 5 invasive squamous cell carcinomas, 5 verrucous hyperplasia (one with a double infection with HPV 4 and 8), 1 pseudoepitheliomatous hyperplasia and 3 giant condylomas. All three giant condylomas were low-risk HPV positive (HPV 6 and 11) and showed active mRNA transcription. None of the HPV-positive samples tested positive for diffuse p16(INK4A) staining. In conclusion, our results do not support a causal role of HPV in the development of verrucous carcinoma. Testing for LR-HPV, particularly HPV 6 and 11, may help in the differential diagnosis of lesions suspicious of verrucous carcinoma as those testing positive for LR-HPV most likely represent giant condylomas.