Background: The dose of levothyroxine (LT4) after total thyroidectomy is usually computed based on actual body weight. However, metabolism through deiodination of thyroid hormones usually occur in the lean body compartment. An optimal dose to reduce delay in achieving target levels is essential to improve quality of life, reduce risk factors and cost. Objectives: Comparison of the efficacy of two methods of computation for the initial levothyroxine dose in patients with differentiated thyroid cancer based on actual body weight vs. lean body mass in achieving thyroid-stimulating hormone (TSH) goals. Methodology: Randomized, single-center, 12-week open label controlled trial among adult patients with differentiated thyroid cancer post total thyroidectomy who underwent radioactive therapy at St. Luke’s Medical Center Quezon City from July-December 2018. Participants were divided into 2 groups - Actual Body Weight (ABW) and Lean Body Mass (LBM). Levothyroxine dose was computed based on ABW vs. LBM and TSH determined at 6th and 12th weeks after. Results: 52 participants (ABW n=26; LBM n=26) were included. ABW group had significantly higher mean LT4 dosage (2.2 mcg/kg) compared to the LBM group (1.4 mcg/kg) (p-value<0.001). ABW group had lower TSH levels at 6th week (5.7 uIU/mL) than LBM group (18.4 uIU/mL) but the difference was not significant. (p-value=0.064). A significantly lower TSH level was observed at week 12 in the ABW group (1.6 uIU/mL) compared to the LBM group (3.8 uIU/mL) (p-value=0.010). However, both methods were not associated with achievement of TSH goal at 6th and 12th week (p-value=0.512 and 0.780, respectively). Conclusion Among patients with differentiated thyroid cancer who underwent 1st time RAI therapy, ABW method of computation for LT4 dosage is better compared to the LBM method due to the lower TSH trend seen at 6th week and statistically significantly lower mean TSH at week 12, although, both method of computations did not achieve target TSH levels at the 6th nor 12th week.