The DNA genomes of four new human papillomaviruses, HPV 75, HPV 76, HPV 77, and HPV 80, have been cloned, sequenced, and characterized. HPV 75, HPV 76 (both HPV 49-related), and HPV 77 (HPV 29-related) were isolated from benign cutaneous warts and HPV 80 (HPV 15-related) from histologically normal skin. HPV 77 has also been demonstrated in dysplastic warts and squamous cell carcinomas of the skin. The sequence data presented in this study led to a proposed modification of the definition of a new HPV type. The high degree of DNA sequence similarity between the E7 ORF of HPV 77 and HPV 29 (97.7%), as opposed to the E6 (82.8%) and L1 (85.3%) ORFs, might suggest conservation of a specific function or a possible recombinational event. Only the E6 and L1 ORFs of HPV 75 and HPV 76 have a similarity lower than 90%, whereas the DNA sequences of their upstream regulatory regions (URRs) share a similarity of 93%. The E7, E1, and E4 ORFs, as well as the URR of HPV 15 and HPV 80, share sequence similarities higher than 90%. Such a divergence in the similarity between different segments of the virus genomes of closely related HPV types has not been noted to date. A detailed comparative sequence analysis was performed. HPV 75, HPV 76, and HPV 80 revealed features characteristic of truly cutaneous HPV types, whereas HPV 77 shared several characteristics with the mucosal HPV types, some of which may have functional consequences.