OBJECTIVE: Compliance to levothyroxine treatment in hypothyroidism is compromised by daily schedule, and a weekly dose may be an alternative. SUBJECTS AND METHODS: This was a randomized, crossover study. Fourteen females were assigned to daily or weekly doses of LT4. After six weeks, they switched regimens. Thyroid parameters were measured at baseline, and after 42 and 84 days. Echocardiogram and hyperthyroidism symptoms were evaluated before and four hours after LT4 intake. RESULTS: In the weekly dose treatment, fT4 levels were higher after taking LT4, and lower seven days after the last dose; by the 6th week there was a small decrease in T3 levels. TSH remained unchanged and there were no hyperthyroidism symptoms or echocardiographic manifestations. CONCLUSION: Weekly dose leads to transient increases in fT4, without hyperthyroidism or cardiac symptoms. That approach seems to be a safe alternative for the treatment of hypothyroidism.