Background: Although thyroid hormone replacement therapy has been a mainstay of endocrinologic therapy, many patients feel unwell despite apparently optimal treatment. Methods and Results: Recently, attempts have been made to improve treatment by administering tri-iodothyroxine (T<sub>3</sub>) in addition to thyroxine. Initial results of a crossover study suggested that combination T<sub>3 </sub>and T<sub>4</sub> therapy was associated with improvements in several measures of quality of life and increased patient preference. Results of subsequent studies have not supported these initially promising findings. Conclusions: At present, combination treatment cannot be recommended. Further clinical studies that are adequately powered and comprised of homogenous patient populations are needed to determine whether any benefits are associated with sustained-release T<sub>3 </sub>preparations.