CONTEXT Glucocorticoids are powerful steroid hormones that regulate development, metabolism, and immune response. However, glucocorticoid unresponsiveness or resistance is observed in the treatment of inflammatory, autoimmune, and lymphoproliferative diseases and significantly limits their efficacy. OBJECTIVE In Cushing's disease, although some glucocorticoid-mediated suppression of pituitary-derived ACTH is seen, corticotroph tumors exhibit relative resistance to glucocorticoid action. We previously demonstrated that testicular orphan receptor 4 (TR4) binds to the pro-opiomelanocortin (POMC) promoter to induce corticotroph tumor POMC expression and ACTH secretion, and we hypothesized that TR4 may interact with glucocorticoid signaling to modulate POMC expression and action. RESULTS Here we demonstrate that TR4 abrogates glucocorticoid receptor (GR)- or dexamethasone-mediated POMC and activator protein-1 transrepression in both murine and human pituitary corticotroph tumor cells. Co-immunoprecipitation studies indicate that TR4 and GR interact directly with each other, resulting in TR4-mediated disruption of GR binding to the POMC promoter. CONCLUSION These results demonstrate that TR4 binds GR to play an important role in glucocorticoid-directed corticotroph tumor POMC regulation in addition to modulating glucocorticoid actions on other GR targets. Characterization of this pathway may offer important insights into glucocorticoid resistance and may identify a novel approach for the treatment of Cushing's disease and the glucocorticoid-resistant states.