A novel papillomavirus was cloned from hyperkeratotic cutaneous lesions of a Persian domestic cat. The Felis domesticus papillomavirus (FdPV-1) genome counts 8300 bp and has a typical genome structure with an early region (E1, E2, E4, E6, E7), a late region (L1, L2), and a noncoding upstream regulatory region (URR or NCR1) between the end of L1 and the beginning of E6. The FdPV-1 also shows an unusual second noncoding region (NCR2) of 1.3 kb, situated between the end of E2 and the beginning of L2. This NCR2 is uniquely related to a similar region in the canine oral papillomavirus (COPV). Phylogenetic analysis places FdPV-1 together with COPV, the cottontail rabbit papillomavirus, human papillomavirus type 1 (HPV-1), and HPV-63 in the group of the benign cutaneous papillomaviruses. The position of FdPV-1 in the phylogenetic tree allows us to hypothesize that already in an early phase of the papillomavirus molecular evolution, a split occurred into viruses with a dual tropism primarily for cutaneous epithelia but also secondarily for mucosal surfaces, and viruses with a specific monotropism for mucosal surfaces. The close relationship between FdPV-1 and COPV, and between their Canidae and Felidae hosts, supports the hypothesis that papillomaviruses have speciated and coevolved together with their hosts throughout vertebrate evolution. A papillomavirus mutation rate of 0.73 to 0.96 x 10(-8) nucleotide substitutions per base per year was calculated.