In order to replicate viruses must invade and hijack host cell defence mechanisms. One of the most important processes that must be hijacked is the cell death pathway including intrinsic apoptosis to prevent premature clearance of infected cells. One strategy is to express proteins homologous in sequence and function to mammalian pro-survival Bcl-2 proteins. Variola virus, the causative agent of smallpox, harbours a homolog of F1L, which in vaccinia virus was shown to be anti-apoptotic by engaging Bim and Bak ¹ . We show that variola virus F1L is unable to bind Bim BH3, and instead shows weak affinity for Bid BH3 as well as Bak and Bax BH3 domains. Despite the ability to engage Bak BH3 peptides, variola F1L only protects against Bax mediated apoptosis in cellular assays. In order to validate this interaction, crystalisation trials have been set up with the Variola F1L:Bax complex. Our results suggest that unlike during vaccinia virus infection, Bim neutralization may not be required by variola virus during infection.