Tip60 (Tat-interactive protein of 60 kDa), a member of MYST family (for its founding members MOZ, YBF2/SAS3, SAS2 and Tip60) histone acetyltransferases, is involved in transcriptional regulation of many genes and diverse signaling transduction. The Tip60 complex consists of multiple subunits, with some implicated in DNA damage and apoptosis. The MYST superfamily members, such as MOZ and MORF, are implicated in the pathogenesis of acute myeloid leukemia. In the present study, Nmi was identified as a novel binding partner for Tip60 by a yeast two-hybrid screen. The association of Tip60 with Nmi was further confirmed by co-immunoprecipitation. Nmi, an interferon and interleukin inducible protein was originally identified as an N-Myc/c-Myc interacting protein. It is expressed in various adult and fetal tissues and in several cancer cell lines with the highest expression in certain myeloid leukemias. Nmi gene is localized on human chromosome 22q13.3 in a region where translocation has been reported in certain human leukemias. The Nmi protein interacts with all the STAT members except STAT2. Although Nmi lacks intrinsic transcriptional activation domain, it functions as an adaptor molecule to enhance STAT-dependent transcription through the recruitment of coactivator CBP/p300. Tip60 interacts with the C-terminus of Nmi in a region essential for Nmi-Nmi homodimerization and Nmi-IFP35 (interferon-inducible protein of 35 kDa) heterodimerization and subcellular localization. Homodimerization of Nmi reduces the interaction of Tip60 with Nmi. Nmi associates with the zinc finger domain of the Tip60, which is important for the transcriptional repression effect of Tip60 on TEL, the translocation E26 transforming-specific (ETS) leukemia. We further showed that Nmi is an unstable protein and is targeted for proteosome-mediated degradation possibly through ubiquitination of its C-terminus. The interaction with Tip60 enhances Nmi stability, which is dependent on the histone acetyltransferase activity of Tip60. Our results suggest that stabilization of Nmi protein through its interaction with Tip60 may be involved in the pathogenesis of certain leukemias.