Selective estrogen receptor modulators (SERMs) are synthetic molecules that exhibit tissue-specific activities. 4-hydroxytamoxifen (OHT) is a first generation SERM that functions as an antagonist in breast cancer cells but displays estrogen-like activities in the uterus and bone. The estrogen-receptor-related receptors (ERR) alpha, beta and gamma are orphan members of the superfamily of nuclear receptors. While the ERRs do not respond to natural estrogens, these receptors recognize the estrogen response element and have been shown to activate and repress gene expression in the absence of exogenously added ligand. Here we show that OHT disrupts the interaction between the orphan estrogen-receptor-related (ERR) receptors beta and gamma and a coregulator protein and abolishes the constitutive transcriptional activity of these receptors in transient transfection assays. In contrast, OHT has no effect on coregulator/ERR alpha interaction or its transcriptional activity. These results demonstrate the existence of a novel nuclear receptor-based pharmacological pathway that may contribute to the tissue-specific activities of OHT.