The three iodothyronine deiodinases (D1, D2, and D3) play major roles in determining the tissue and cellular content of the active thyroid hormone, T3. The D1 and D2 5'-deiodinate T4 to T3 and the D3 5-deiodinates T4 and T3 to inactive forms. 5'-Deiodinase-deficient mice (D1/D2KO) have a mild gross phenotype, whereas D3-deficient mice (D3KO) exhibit significant phenotypic abnormalities of the hypothalamic/pituitary/thyroid axis and other organ systems and are not viable in some background strains. The goal of this study was to perform an initial assessment of the phenotype of mice devoid of all deiodinases (D1/D2/D3KO) and determine whether the marked phenotypic abnormalities of the D3KO mouse are exacerbated or mitigated by the absence of the D1 and D2. Relative to D3KO mutants, survival, growth, and fertility were improved in the D1/D2/D3KO mice, although considerably impaired relative to wild-type and D1/D2KO animals. The triple deiodinase-deficient mice also demonstrated normal brain T3 content at postnatal day 6, normal cerebellar expression of the T3-responsive gene hairless at postnatal day 21, and near normalization of their serum thyroid hormone levels as adults, parameters that are abnormal in either the D3KO or the D1/D2KO mutants. These studies demonstrate that within the supportive environment of a research vivarium, mice lacking all three deiodinases can be bred and survive and that at least some of the phenotypic abnormalities resulting from a deficiency of either the D3 5-deiodinase, or the D1 and D2 5'-deiodinase, are mitigated by the simultaneous lack of all three enzymes.