We have identified two novel proteins that interact specifically with the C‐terminal repression domain of Interferon Regulatory Factor‐2 (IRF‐2). These proteins, which we term IRF‐2 binding proteins 1 and 2 (IRF‐2BP1 and IRF‐2BP2, the latter having two splicing isoforms, A and B), are nuclear proteins, and have the properties of IRF‐2‐dependent transcriptional co‐repressors that can inhibit both enhancer‐activated and basal transcription in a manner that is not dependent upon histone deacetylation. IRF‐2BP1 and IRF‐2BP2A/B contain an N‐terminal zinc finger and a C‐terminal RING finger domain of the C3HC4 subclass, but show no homology to other known transcriptional regulators; they therefore define a new family of co‐ repressor proteins. An alternatively spliced form of IRF‐2 that lacks two amino acids (valines 177 and 178) in the central portion of the protein (IRF‐2[S]) cannot bind to these co‐repressors and cannot mediate repression despite having the same C‐ terminal repression domain as IRF‐2, suggesting that the relative conformation of the DNA binding domain and the C‐terminal region of IRF‐2 is crucial for transcriptional repression.