The KBF1 factor, which binds to the enhancer A located in the promoter of the mouse MHC class I gene H‐2Kb, is indistinguishable from the p50 DNA binding subunit of the transcription factor NF‐kappa B, which regulates a series of genes involved in immune and inflammatory responses. The KBF1/p50 factor binds as a homodimer but can also form heterodimers with the products of other members of the same family, like the c‐rel and v‐rel (proto)oncogenes. The dimerization domain of KBF1/p50 is contained between amino acids 201 and 367. A mutant of KBF1/p50 (delta SP), unable to bind to DNA but able to form homo‐ or heterodimers, has been constructed. This protein reduces or abolishes in vitro the DNA binding activity of wild‐type proteins of the same family (KBF1/p50, c‐ and v‐rel). This mutant also functions in vivo as a trans‐acting dominant negative regulator: the transcriptional inducibility of the HIV long terminal repeat (which contains two potential NF‐kappa B binding sites) by phorbol ester (PMA) is inhibited when it is co‐transfected into CD4+ T cells with the delta SP mutant. Similarly the basal as well as TNF or IL1‐induced activity of the MHC class I H‐2Kb promoter can be inhibited by this mutant in two different cell lines. These results constitute the first formal demonstration that these genes are regulated by members of the rel/NF‐kappa B family.