Current guidelines recommend that hypothyroid patients should be treated with levothyroxine, which in the vast majority of the cases leads to resolution of the symptoms and normalization of serum free T₄(FT₄), T₃ and TSH levels. However, a small group of hypothyroid patients remain symptomatic for neurocognitive dysfunction despite normal serum FT₄ and TSH, which could be explained by localized brain hypothyroidism. More than half of the T₃ in the brain is produced locally via the action of the type II deiodinase (D₂) and variability/defects in this pathway could explain the residual symptoms. If this rationale is correct, adding liothyronine to the replacement therapy could prove beneficial. However, with a few exceptions, several clinical trials failed to identify any beneficial effects of combined therapy. More recently, the results of a large clinical trial revealed a better neurocognitive outcome with combined therapy only in hypothyroid patients carrying a polymorphism in the DIO2 gene. This obviously needs to be confirmed by other groups but it is tempting to speculate that combined levothyroxine and liothyronine has a place in the treatment of hypothyroidism, for some.