Human papillomaviruses (HPV) are causative agents in a variety of human diseases; for example over 99% of cervical carcinomas contain HPV DNA sequences. Often in cervical carcinoma the HPV genome is integrated into the host genome resulting in unregulated expression of the viral transforming proteins E6 and E7. Therefore viral integration is a step towards HPV induced carcinogenesis. Integration of the HPV genome could occur following double-strand DNA breaks that could arise during viral DNA replication. We investigated the fidelity of HPV 16 E1 and E2 mediated DNA replication of non-damaged and UVC damaged templates in a variety of cell lines with different genetic backgrounds; C33a (derived from an HPV negative cervical carcinoma), XP30RO (deficient in the by-pass polymerase h), XP30h (expressing a restored wild type polh), XP12RO (nucleotide excision repair defective) and MRC5 (derived from a 14 week old human foetus). The results demonstrate that the fidelity of E1 and E2 mediated DNA replication is reflective of the genetic background in which the assays are carried out. For example, restoring polh to the XP30 cell line results in a three-fold drop in the number of mutants obtained following replication of a UVC damaged template. A relatively high percentage of the mutant replicated molecules arise as a result of genetic rearrangement. This is the first time such studies have been carried out with an HPV replication system and the results are discussed in the context of the HPV life cycle and what is known about HPV genomes in human cancers.