Abstract 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 α (TRα) gene, yielding Pax8−/−TRαo/o double-knockout animals. This observation has led to the hypothesis that unliganded TRα1 might be responsible for the lethal phenotype observed in Pax8−/− animals. In this study we report the generation of Pax8−/−TRα1−/− double-knockout mice that still express the non-T3-binding TR isoforms α2 and Δα2. 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−/−TRα1−/− 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 TRα1 aporeceptor, but, rather, suggest a more complex mechanism involving TRα2 and an unliganded TR isoform.