The Pax8(-/-) mouse provides an ideal animal model to study the consequences of congenital hypothyroidism, because its only known defect is the absence of thyroid follicular cells. Pax8(-/-) mice are, therefore, completely athyroid in postnatal life and die around weaning unless they are substituted with thyroid hormones. As reported recently, Pax8(-/-) mice can also be rescued and survive to adulthood by the additional elimination of the entire thyroid hormone receptor alpha (TRalpha) gene, yielding Pax8(-/-)TRalpha(o/o) double-knockout animals. This observation has led to the hypothesis that unliganded TRalpha1 might be responsible for the lethal phenotype observed in Pax8(-/-) animals. In this study we report the generation of Pax8(-/-)TRalpha1(-/-) double-knockout mice that still express the non-T(3)-binding TR isoforms alpha2 and Deltaalpha2. These animals closely resemble the phenotype of Pax8(-/-) mice, including growth retardation and a completely distorted appearance of the pituitary with thyrotroph hyperplasia and hypertrophy, extremely high TSH mRNA levels, reduced GH mRNA expression, and the almost complete absence of lactotrophs. Like Pax8(-/-) mice, Pax8(-/-)TRalpha1(-/-) compound mutants die around weaning unless they are substituted with thyroid hormones. These findings do not support the previous interpretation that the short life span of Pax8(-/-) mice is due to the negative effects of the TRalpha1 aporeceptor, but, rather, suggest a more complex mechanism involving TRalpha2 and an unliganded TR isoform.