Transcription of the E6-E7 genes of human papillomavirus type 11 (HPV-11), HPV-16 and HPV-18 is specific to epithelial cells. This mechanism originates from synergism between different transcription factors such as AP-1, NFI and Sp1, which occur in many different cell types, but whose activity is biased in favour of epithelial cells. In this study, the transcriptional regulation of 14 different papillomavirus types in the absence of the viral E2 transcription factor was compared. Genital HPV types, including high-risk, low-risk and common wart-associated HPVs, were found to have strong epithelial specific enhancers, irrespective of mucosal or skin target cell and pathology. Skin specific non-genital HPVs, like HPV-1 and HPV-8, as well as bovine papillomavirus type 4 (BPV-4), had much lower enhancer activity. Contiguous genomic segments including the enhancer and the E6 promoter of genital as well as non-genital papillomaviruses generally had very low transcriptional activities, presumably due to silencers between enhancer and promoter sequences. This generalization applies to all cell types tested in spite of significant quantitative differences between the cervical carcinoma-derived cell line HeLa, the skin-derived cell line HaCat, undifferentiated and differentiated primary keratinocytes. The only enhancer with activity in fibroblasts was identified in BPV-1, apparently a reflection of the broader target cell specificity of this virus. The low transcriptional activity of papillomaviruses most likely reflects the low gene expression required during most or even all parts of the life-cycle of these viruses.