Epstein-Barr virus has been linked to several types of human cancer including Burkitt's lymphoma and nasopharyngeal carcinoma but the mechanisms by which the virus might contribute to cancer remain obscure. Here we consider the possibility that EBNA-1, which is expressed in both tumours, directly transactivates cell genes. The EBNA-1 protein was tested for transcription transactivation domains and the human genome was screened for high-affinity EBNA-1-binding sites that might mediate transactivation. None were found, although novel low-affinity-binding sites in the EBV genome were detected. We also investigated the expression of BHRF1, the viral homologue to bcl-2, in epithelial cells and showed that it is expressed in vivo in the EBV replication found in oral hairy leukoplakia. A novel hypothesis is proposed for nasopharyngeal carcinoma in which BHRF1 expression protects cells against apoptotic death caused by environmental DNA damaging agents and thus contributes to the early stages of cancer development.