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Background: The current approach for calculating the starting dose of levothyroxine (LT4) after total thyroidectomy is based on the patient's body weight (BW). The aim of the study was to identify the major predictive factors of LT4 requirement and to elaborate a new method to improve the accuracy of the LT4 starting dose after total thyroidectomy. Methods: The study consists of two parts. The first part consisted of the retrospective identification of 92 adult patients (retrospective cohort) who had undergone a total thyroidectomy for benign disease and who had begun LT4 treatment at a dose of 1.6 μg/kg/day. Adjustments to optimize the LT4 dose were then performed at the post-surgery follow-up on the basis of serum thyrotropin (TSH) levels. The results of this retrospective analysis were used to formulate a nomogram for a proper calculation of the LT4 starting dose that was then used prospectively in the second part of the study on 31 consecutive patients (prospective cohort). Results: At the first follow-up, 37 (40%) patients from the retrospective cohort were euthyroid. Univariate analysis indicated significant correlations between the optimal dose of LT4 and BW, body mass index (BMI), age, preoperative mean corpuscular volume, and free triiodothyronine (fT3). The optimal dose of LT4, analyzed for BMI and age, showed an inverse relationship with these two parameters, and ranged from 1.4 to 1.8 μg/kg/day. In the prospective cohort, the use of an age- and BMI-related nomogram improved the prediction of the optimal LT4 starting dose, with 68% of patients being euthyroid at the first follow-up compared to 41% of patients reported to have reached euthyroid state using the best strategy proposed in the literature. Conclusions: This study confirms that BW is not the only variable for predicting LT4 requirement, as it decreases with the increase in age and BMI, probably due to the relative decrease of lean body mass. A new correlation between optimal dose and presurgical levels of fT3 and mean corpuscular volume was observed. We propose an easy and more efficient method of calculating LT4 starting dose after total thyroidectomy for benign disease. [ABSTRACT FROM AUTHOR]