THYROID hormone receptor β–deficient (TRβ–/–) mice have defective auditory-evoked brain stem responses (ABR). Sincein vitro, TRβ binds to DNA as homodimers or as heterodimers with retinoid X receptors (RXRs), we investigated whether the TRβ–/– phenotype may reflect loss of RXR-TRβ heterodimer or TRβ homo-dimer function. Normal ABR thresholds were recorded in RXRβ–/–, RXRγ–/– RXRα–/+ and RXR compound mutant mice. When RXR mutations were introduced onto TRβ–/+ or TR–/– backgrounds, thresholds were dictated solely by TRβ and not RXR genotype. TRβ–/– mice also over-produce thyroid hormones and thyroid stimulating hormone; however, levels of these hormones were unaltered by RXR mutations. This suggests that, contrary toin vitromodels, RXRs may be dispensable and that TRβ may functionin vivoby an RXR-independent mechanism in the auditory system and pituitary–thyroid axis.