The NF-kappaB pathways have been implicated in tumorigenesis in several lymphoid malignancies, including non-Hodgkin's and Hodgkin's lymphomas. However, the antiapoptotic functions and the mechanism responsible for signaling through each NF-kappaB pathway remain to be elucidated. In the current study, lymphoma cell lines with constitutively active NF-kappaB were found to be resistant to inducers of the extrinsic and intrinsic apoptosis pathways. Resistance to cell death resulted from blocks early and late in the apoptosis cascade. Several NF-kappaB target genes were overexpressed in these cell lines, including Bcl-xL, Fas-associated death domain-like IL-1beta-converting enzyme inhibitor protein, cellular inhibitor of apoptosis, and X inhibitor of apoptosis. Inhibition of the canonical or noncanonical NF-kappaB pathways with small interfering RNAs or adenovirus expressing a stable form of inhibitor of NF-kappaB (IkappaB) enhanced sensitivity to apoptosis inducers and resulted in lower levels of Bcl-xL or Fas-associated death domain-like IL-1beta-converting enzyme inhibitor protein, cellular inhibitor of apoptosis, and X inhibitor of apoptosis. These findings demonstrate an important role of both NF-kappaB pathways in mediating resistance to apoptosis and distinctive antiapoptotic downstream target gene profiles responsible for this effect.