TGFβ1 treatment of B cell lymphomas decreases c-myc gene expression and induces apoptosis. Since we have demonstrated NF-κB/Rel factors play a key role in transcriptional control of c-myc, we explored the effects of TGFβ1 on WEHI 231 immature B cells. A reduction in NF-κB/Rel activity followed TGFβ1 treatment. In WEHI 231 and CH33 cells, we observed an increase in IκBα, a specific NF-κB/Rel inhibitor, due to transcriptional induction. Engagement of surface CD40 or ectopic c-Rel led to maintenance of NF-κB/Rel and c-Myc expression and protection of WEHI 231 cells from TGFβ1-mediated apoptosis. Ectopic c-Myc expression overrode apoptosis induced by TGFβ1. Thus, downmodulation of NF-κB/Rel reduces c-Myc expression, which leads to apoptosis in these immature B cell models of clonal deletion. The inhibition of NF-κB/Rel activity represents a novel TGFβ signaling mechanism.