Abstract Background Hypothyroidism is a common disorder, with a prevalence of approximately 5% and incidence of approximately 250 /100,000 per year in the adult population both prevalence and incidence keep raising. Levothyroxine is the recommended hormone for replacement therapy in both overt and subclinical hypothyroidism. Aim of the Work Levothyroxine (L-T4) is the standard therapy of hypothyroidism. Our purpose was to compare the efficacy of the L-T4 sublingual tablet administration to standard oral L-T4 tablet in hypothyroid patients with refractory hypothyroidism. Subjects and Methods Our study was conducted on 40 patients who were documented to be refractory to oral thyroxine age range 18- 55, 38 females and 2males. Patients were recruited from Endocrinology and Metabolism clinic at Ain-Shams University and Internal medicine outpatient clinic at 6th of October University during the period from June 2019 to October 2020 Informed consent was obtained from all subjects. Results In our study showed a significant decrease in mean TSH (write the figures) on sublingually administrated levothyroxine tablets compared to orally administrated levothyroxine tablets and a significant rise of mean free T4 after 1 week. yet after 6 weeks there was insignificant difference of FT4 compared to oral levothyroxine. Patients who were antiparietal cell antibody positive demonstrated a non significant rise of free T4 level with almost doubling of level compared to oral levothyroxine at 1 week and 6 weeks interval, this was associated with a significant decline of serum TSH at 6 weeks interval. Also This was associated with a significant improvement in hypothyroidism symptoms Conclusion In conclusion, our study indicated that sublingual route for LT4 tablet administration was safe and innovative route for LT4 administration,it could improve compliance, overcome many obstacles with oral administration for intake with food,coffee,drug interaction and GI malabsorption.