Introduction: We conducted this controlled trial to investigate whether combined therapy with levothyroxine and liothyronine in primary hypothyroidism, would lead to improvements in general health, quality of life, psychological problems and metabolic changes. Materials and Methods: This study was a double blinded randomized control trial. Patients were invited to participate if they were between the ages of 18 and 60 years, and if they had been receiving treatment for primary hypothyroidism for at least 6 months, including a stable dose of levothyroxine for at least 3 months, and had normal serum thyroid hormone levels. Patients were randomized to receive combined levothyroxine plus liothyronine (patients in this group decreased their usual daily dose of levothyroxine by 50 μg and began taking 6.25 μg of liothyronine twice daily) or to continue their usual dose of levothyroxine. Treatment duration was 4 months. Weight, height, heart rate, blood pressure, total Cholesterol, LDL, HDL, Triglycerides, serum TSH, total T4, and total T3 levels were measured before and after of study. All patients completed the General Health Questionnaire -28 (GHQ-28) before and after the trial. Results: Seventy-one participants were randomized into the 2 groups, and 60 completed the study. In the combined therapy group, serum T4 levels fell and serum T3 levels rose (P<.001), although both levels remained within normal limits. Serum TSH levels were similar in both groups at baseline and at 4 months. There were no differences between weight, heart rate, blood pressure and lipid profiles of two groups. For the GHQ-28, the overall score was similar but the anxiety/insomnia subscale was significantly higher (indicating worse psychological well-being) for combined treatment compared with T4 alone (P=0.037). Conclusion: The only biochemical change was the expected rise in serum T3 levels and fall in serum T4 in the combined therapy group, because the blood samples were drawn only 1-2 hour after the morning dose of liothyronine. In conclusion, we found no evidence that combined T4/T3 replacement, resulted in improved well-being, general health, quality of life and lipid profile compared with T4 alone. T4 should remain the standard treatment for hypothyroidism.