Epstein-Barr virus (EBV), a B cell growth-transforming human herpesvirus, is linked to several human malignancies, in particular endemic Burkitt lymphoma (eBL). Though always present in this tumour, EBV‟s role remains unclear since, in most cases, viral gene expression is restricted to the viral genome maintenance protein, EBNA1 and the non-coding EBERs, BARTs and BART-derived microRNAs (Latency I infection). This study first asked whether EBV was required for continued BL growth in vitro by screening a panel of Latency I BL cell lines for EBV-loss clones. Such clones were isolated from 5/12 BL lines tested. In each case these cells proved to be more sensitive to apoptosis than their EBV-positive counterparts, an effect which could be reversed by reinfection with a recombinant EBV. Cellular gene expression profiling of EBV-positive and EBV-loss clones on four BL backgrounds revealed transcriptional differences but none that were common to all four tumours. To examine the responsible viral function, a doxycycline-regulated vector was used to express EBNA1 and EBERs at physiologic and supra-physiologic levels in EBV-loss cells on two BL backgrounds. Contrary to previous reports, neither EBNA1 nor EBERs conferred apoptosis resistance, a result which implicates the BARTs or BART-derived microRNAs as novel anti-apoptotic effectors.