Replication of human papillomavirus (HPV) is thought to require the expression of components of the host cell DNA replication apparatus. The expression of the mRNA encoding the DNA replication-dependent histones H2B, H3, and H4 was investigated in a series of verrucae using an FITC-labelled oligonucleotide cocktail for in situ hybridization, to explore the possibility of HPV inducing the transcription of host cell histones. In contrast to normal epidermis, in which the majority of histone mRNA labelling was confined to basal cells, a bimodal distribution of histone positivity was observed in all verrucae. In addition to basal hyperproliferation-associated labelling, numerous positive suprabasal cells were found within the stratum spinosum. By contrast, in another hyperproliferative lesion, psoriasis, the labelling pattern was similar to that found in the normal controls, with characteristic basal hyperproliferation but no evidence of suprabasal labelling. The presence of HPV replication in every verruca and its absence from all controls of normal and psoriatic skin were demonstrated immunohistochemically, using a polyclonal antibody to the viral capsid proteins. It is proposed that the presence of histone mRNAs in differentiated suprabasal keratinocytes of verrucae is due to the virus turning on parts of the cellular apparatus in order for it to replicate in the absence of cellular proliferation. The results also emphasize that when assessing proliferation with in situ hybridization for histone mRNA, the possibility of HPV causing the labelling of non-proliferating cells should be considered.