Estrogen-related receptor gamma (ERRgamma) is an orphan nuclear receptor lacking identified natural ligands. However, 4-hydroxytamoxifen and diethylstilbestrol were recently shown to bind to and inhibit ERRgamma activity. ERR activates transcription constitutively as a monomer. We show here that ERRgamma forms also dimers via its ligand-binding domain. Homodimerization enhances the transcriptional activity. In contrast, heterodimerization with the related receptor ERRalpha inhibits the activities of both ERRgamma and ERRa. The inverse ERRgamma agonist 4OHT further inhibits the activity of the ERRgamma-ERRalpha heterodimer, indicating that 4OHT may modulate ERRalpha signaling via ERRgamma. Receptor dimerization thus modulates the transcriptional activities of ERRs. (C) 2004 Elsevier Inc. All rights reserved.