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Objective: We compare the effect of daily versus weekly levothyroxine (LT4) replacement on thyroid function test (TFT) in hypothyroid patients at a tertiary care centre in Haryana. Materials and Methods: This was a randomised crossover study in which 100 hypothyroid patients on a stable LT4 dose were divided into 2 groups of 50 each. In group I, patients were given daily therapy for 6 weeks and then shifted to weekly therapy for the next 6 weeks. In group II, patients were given LT4 once a week for 6 weeks and then switched to daily therapy for the next 6 weeks. TFT, quality of life (QOL), and hyperthyroidism symptom scale (HSS) score of patients were compared in each group at 0, 6, and 12 weeks. Results: TFT remained within the normal range, but TSH increased (group I, daily 2.8 ± 1.4 mIU/L, weekly 3.9 ± 1.1 mIU/L, p = 0.001; group II, weekly 4.6 ± 1.1 mIU/L, daily 2.7 ± 1.2 mIU/L, p = <0.001) and T3/T4 decreased with weekly therapy as compared to daily therapy. No significant difference in HSS score was found between daily and weekly administration of LT4. With weekly therapy, QOL showed improvement in bodily pain, vitality, mental health, and social functioning. Conclusion: Once-weekly LT4 administration is a reasonable alternative for patients, especially for those who have issues with compliance.