The thyroid hormone (TH)-inducible expression of some genes has recently been shown to be enhanced by 9-cis-retinoic acid (9-cis-RA) receptor (RXR). This effect appears to be at least partially elicited by the ability of RXR to heterodimerize with TH receptor (THR) and enhance its binding to the cis-acting thyroid hormone responsive elements (TREs) found within those genes. However, whether RXR beta enhances TH/THR-mediated transactivation of all Tre-containing genes, and if RXR has any effect on TH-dependent negative regulation are not known. In the present study, we show that the TH/THR-inducible expression of the myelin basic protein (MBP) gene is not enhanced by RXR beta, despite high affinity binding of the RXR beta.THR alpha heterodimer to the MBP-TRE. We also demonstrate that RXR beta reverses the TH/THR-dependent down-regulation mediated by the negative TRE found within the promoter of the mouse thyroid stimulating hormone gene (TSH). The ligand for RXR beta (9-cis-RA), either alone or in combination with TH, did not enhance the transcription mediated by either the MBP-TRE, TSH-TRE, or the malic enzyme (ME)-TRE. However, the ME-TRE is known to confer RXR beta-dependent enhancement of TH-induced gene expression. Thus, the capacity of RXR beta to modulate TH-dependent transcriptional regulation depends upon the nature of the TRE.