The c- abl proto-oncogene encodes a nonreceptor tyrosine kinase involved in many cellular processes, including signaling from growth factor and antigen receptors, remodeling the cytoskeleton, and responding to DNA damage and oxidative stress. Many downstream pathways are affected by c-Abl. Elevated c-Abl kinase activity can inhibit NF-κB activity by stabilizing the inhibitory protein IκBα, raising the possibility that c-Abl-deficient cells might have increased NF-κB activity. We examined the levels of NF-κB activity in primary mouse embryonic fibroblasts (MEFs) derived from wild-type and c-Abl knockout mice and found that the knockout MEFs indeed exhibited elevated NF-κB activity in response to stimulation as well as constitutively elevated NF-κB activity. Thus, endogenous c-Abl is a negative regulator of basal and inducible NF-κB activity. Examination of various points of NF-κB regulation revealed that unstimulated c-Abl knockout MEFs do not exhibit an increase in IκBα degradation, p65/RelA nuclear translocation, or DNA binding of NF-κB subunits. They do, however, show reduced levels of the histone deacetylase HDAC1, a negative regulator of basal NF-κB activity. Unstimulated c-Abl knockout MEFs are less responsive to induction of NF-κB activity by trichostatin A, an HDAC inhibitor, suggesting that c-Abl might play a role in the HDAC-mediated repression of basal NF-κB activity.