Corepressor N-CoR (nuclear receptor corepressor) and the highly related protein SMRT (silencing mediator of retinoid and thyroid hormone receptor) play important roles in different biological processes including proliferation, differentiation, and development. Understanding the biological function of these corepressors requires identification and characterization of their interacting proteins. Here we report the characterization of a novel N-CoR-interacting protein, JMJD2A (previously known as KIAA0677). JMJD2A is an evolutionarily conserved nuclear protein containing many functionally unknown domains. JMJD2A directly interacts with the N-terminal region of N-CoR through a small NID (N-CoR interaction domain) both in vitro and in vivo. Despite its copurification with N-CoR, JMJD2A is not a core subunit of the stable multiprotein N-CoR complex and is not required for N-CoR-mediated repression by thyroid hormone receptor. By chromatin immunoprecipitation cloning, we identified the human achaete scute-like homologue 2 (ASCL2/Hash2) gene as a gene regulated by JMJD2A. ASCL2 is a basic helix-loop-helix transcription factor whose mouse homolog is encoded by an imprinted gene highly expressed during the development of extraembroynic trophoblast lineages but repressed in other tissues and is essential for proper placental development. We demonstrated that JMJD2A selectively represses the expression of the ASCL2 gene but not other imprinted genes in the same imprinted locus in HeLa cells and that this repression required a functional N-CoR complex and the tandem Tudor domain of JMJD2A. Like N-CoR, JMJD2A is widely expressed in various mouse tissues. Our data indicate that JMJD2A makes use of the N-CoR complex to repress transcription and suggest that JMJD2A together with N-CoR could play a role in repressing ASCL2 expression in various tissues.