Corepressors and coactivators can modulate the dose-response curve and partial agonist activity of glucocorticoid receptors (GRs) complexed with agonist and antagonist steroids, respectively, in intact cells. We recently reported that GR-antagonist complexes bind to the coactivator TIF2, (transcriptional intermediary factor 2), which is consistent with the whole-cell effects of coactivators being mediated by direct interactions with GR complexes. We now ask whether the whole-cell modulatory activity of corepressors also entails binding to both GR-agonist and -antagonist complexes and whether the association of corepressors and coactivators with GR complexes involves competitive equilibrium reactions. In mammalian two-hybrid assays with two different cell lines and in cell-free pull-down and whole-cell immunoprecipitation assays, the corepressors NCoR (nuclear receptor corepressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptor) associate with agonist and antagonist complexes of GRs. Both N- and C-terminal regions of GR are needed for corepressor binding, which requires the CoRNR box motifs that mediate corepressor binding to other nuclear/steroid receptors. Importantly, whole-cell GR interactions with corepressors are competitively inhibited by excess coactivator and vice versa. However, the regions of the coactivator TIF2 that compete for GR binding to corepressor and coactivator are not the same, implying a molecular difference in GR association with coactivators and corepressors. Finally, when the whole-cell ratio of coactivators to corepressors is altered by selective cofactor binding to exogenous thyroid receptor beta +/- thyroid hormone, the GR dose-response-curve and partial agonist activity are appropriately modified. Such modifications are independent of histone acetylation. We conclude that mutually antagonistic equilibrium interactions of corepressors and coactivators modulate the dose-response curve and partial agonist activity of GR complexes in a manner that is responsive to the intracellular ratio of these two classes of cofactors. This modulation provides an attractive mechanism for differential control of gene expression during development, differentiation, homeostasis, and endocrine therapies.