The peroxisome proliferator-activated receptor gamma (PPARgamma) is a central regulator of adipogenesis and recruits coactivator proteins in response to ligand. However, the role of another class of nuclear cofactors, the nuclear receptor corepressors, in modulating PPARgamma transcriptional activity is less clear. Such corepressors include the nuclear receptor corepressor (NCoR) and the silencing mediator of retinoid and thyroid hormone receptors (SMRT). Our data suggest that PPARgamma recruits SMRT and NCoR in the absence of ligand and that these corepressors are capable of down-regulating PPARgamma-mediated transcriptional activity. The addition of the PPARgamma ligand pioglitazone results in dissociation of the PPARgamma-corepressor complex. To define the role of SMRT and NCoR in PPARgamma action, 3T3-L1 cells deficient in SMRT or NCoR were generated by RNA interference. When these cells are exposed to differentiation media, they exhibit increased expression of adipocyte-specific genes and increased production of lipid droplets, as compared with control cells. These data suggest that the nuclear receptor corepressors decrease PPARgamma transcriptional activity and repress the adipogenic program in 3T3-L1 cells.