Hodgkin/Reed-Sternberg (H/RS) cells are believed to represent clonal progeny of Germinal Centre B cells that have escaped negative selection by evading apoptosis. Aberrant constitutive activity of the transcription factor NF-κB plays a key role in the pathogenesis of Hodgkin's Lymphoma (HL), conferring a survival advantage on H/RS cells.Bfl-1is a pro-survival NF-κB target gene from the Bcl-2 family of apoptosis-regulating proteins. Here, we report thatbfl-1(also known asA1orGRS) is frequently expressed in primary H/RS cells from HL tumor biopsies and that elevatedbfl-1expression is a feature of H/RS derived cell lines. We show thatbfl-1is an NF-κB target gene in this cell context and that this regulation is effected through a p65-binding DNA element located in its promoter. We demonstrate that ectopic Bfl-1 can rescue cultured H/RS cells from apoptosis induced by pharmacological inhibitors of NF-κB, and that knockdown ofbfl-1potentiates the pro-apoptotic effect of these agents. These findings are the first indication that Bfl-1 plays a crucial role in setting the elevated threshold of resistance of this malignant cell type to apoptosis.