The papillomavirus E2 protein tethers viral genomes to host mitotic chromosomes to ensure genome maintenance. We have identified the bromodomain protein Brd4 as a major cellular interacting partner of the bovine papillomavirus E2. Brd4 associates with mitotic chromosomes and colocalizes with E2 on mitotic chromosomes. The site of E2 binding maps to the C-terminal domain of Brd4. Expression of this C-terminal Brd4 domain functions in a dominant-negative manner to abrogate the colocalization of E2 with Brd4 on mitotic chromosomes, to block association of the viral episomes with Brd4, and to inhibit BPV-1 DNA-mediated cellular transformation. Brd4 also associates with HPV16 E2, indicating that Brd4 binding may be a shared property of all papillomavirus E2 proteins. The interaction of E2 with Brd4 is required to ensure the tethering of viral genomes to the host mitotic chromosomes for persistence of viral episomes in PV-infected cells.