Abstract Disclosure: M. Nassar: None. A. Hassan: None. M.T. Desouki: None. S. Ramadan: None. M.A. Hassan: None. A. Chaudhuri: None. Background: Many patients with hypothyroidism experience persistent symptoms despite normalized TSH levels, which highlights the need for alternative treatment strategies. This study aims to evaluate the effectiveness of combined T4 and T3 therapy or desiccated thyroid (DTE) compared to T4 monotherapy, with a focus on thyroid profile, lipid profile, and quality of life metrics, including the 36-point thyroid symptom questionnaire (TSQ-36), Beck Depression Inventory (BDI) scores, and General Health Questionnaire (GHQ)-28 scores. Methods: A systematic literature search was conducted using a Boolean strategy on the following databases: Embase, Medline/PubMed, and Web of Science. The search included results from the inception of each database until 11/23/2023. We used the following keywords: "Armour Thyroid," OR "Thyroid Extract," OR "Natural Desiccated Thyroid," OR "Nature-Throid," "Desiccated Thyroid," OR "NP Thyroid," OR "Synthroid," OR "Levothyroxine," OR "Liothyronine," "Cytomel," OR "Thyroid USP," OR "Unithroid." AND "hypothyroidism. " We only included RCTs. We excluded non-English articles. Results: Initially, 6,394 records were identified. After removing 477 duplicate records, 5,917 records underwent title and abstract screening, excluding 5,874 records. The full texts of the remaining 43 articles were examined for eligibility, excluding 27 articles. Ultimately, 16 studies met the inclusion criteria and were incorporated into our analysis. We included two studies on desiccated thyroid and 15 studies on combined therapy. In this meta-analysis, combination therapy with T4+T3 revealed a significant reduction in free T4 levels (mean difference (MD): -0.34; 95% CI: -0.47, -0.20), total T4 levels (mean difference: -2.20; 95% CI: -3.03, -1.37), and GHQ-28 scores (MD: -2.89; 95% CI: -3.16, -2.63) compared to T4 monotherapy. Total T3 levels increased significantly in combined therapy (MD: 29.82; 95% CI: 22.40, 37.25). The analyses demonstrated moderate to high heterogeneity. There was no significant difference in heart rate, SHBG, TSH, lipid profile, TSQ-36, or BDI score. DTE significantly increased serum total T3 levels (MD: 50.90; 95% CI: 42.39, 59.42) and significantly decreased serum total T4 (MD: -3.11; 95% CI: -3.64, -2.58) and free T4 levels (MD: -0.50; 95% CI: -0.57, -0.43) compared to T4 monotherapy. Moreover, DTE treatment showed a modest increase in TSH levels (MD: 0.49; 95% CI: 0.17, 0.80). The analyses indicated low heterogeneity. There was no significant difference in heart rate, SHBG, lipid profile, TSQ-36, GHQ-28, or BDI score. Conclusions: Our study revealed that combined therapy and DTE lead to higher T3 and lower T4 levels compared to T4 monotherapy in hypothyroidism. However, no significant effects on heart rate, lipid profile, or quality of life were noted. Given the heterogeneity of results, personalized treatment approaches are recommended. Presentation: 6/1/2024