A key activity of the p53 protein during suppression of cell growth is its ability to stimulate transcription from promoters of cellular genes which contain a p53 responsive element. The E6 proteins from the oncogenic associated Human Papillomaviruses (HPVs) have been shown to inhibit specifically the p53 transcriptional activation and this has been proposed as a mechanism whereby the virus prevents the suppression of cell cycle progression and the induction of apoptosis. However, the mechanism by which E6 exercises this function is unknown, as is the ability of E6 to associate with different oligomeric forms of p53. In this study we demonstrate that E6 induces changes within the p53 protein which result both in inhibition of DNA binding and in dissociation of p53 protein previously bound to the DNA. These activities correlate exactly with the ability of E6 to inhibit p53 transcriptional activation and are independent of the ability of E6 to direct the degradation of the p53 protein. Further, we show that E6 labels wild type tetrameric and dimeric forms of p53 proteins for ubiquitin mediated degradation more readily than monomeric forms of the protein. However, in vivo analyses indicate that E6 is capable of inhibiting the transcriptional activation induced by the tetrameric, dimeric and monomeric forms of p53.