IKB is an inhibitory protein that stabilizes the inducible cytoplasmic form of the NF-KB transcription factor. We have purified lKB-a, a major form of IKB with an apparent molecular size of 37 kd, from cytosol of human placenta. A second chromatographically distinct form, IKB-8, was partially purified and found to be more basic and 3-8 kd larger than the a form. The occurrence of distinct forms of IKB could explain how NF-KB can be activated in response to various agents that signal via different intracellular messenger systems. Both It&-a and-8 exclusively inactivated NF-KB containing the non-DNA binding 85 kd subunit and, within minutes, could dissociate a high affinity complex of NF-KB with its cognate DNA. On the assumption that free lKB-a and-8 can enter the nucleus, these proteins could rapidly release NF-KB from high affinity binding sites in enhancer and promoter elements, thereby terminating NF-KB-dependent initiation of gene expression.