Context: Patients previously treated with desiccated thyroid extract (DTE), when being switched to levothyroxine (L-T4), occasionally did not feel as well despite adequate dosing based on serum TSH levels. Objective: Our objective was to investigate the effectiveness of DTE compared with L-T 4 in hypothyroid patients. Design and Setting: We conducted a randomized, double-blind, crossover study at a tertiary care center. Patients: Patients (n = 70, age 18-65 years) diagnosed with primary hypothyroidism on a stable dose of L-T4 for 6 months were included in the study. Intervention: Patients were randomized to either DTE or L-T4 for 16 weeks and then crossed over for the same duration. Outcome Measures: Biochemical and neurocognitive tests at baseline and at the end of each treatment period were evaluated. Results: There were no differences in symptoms and neurocognitive measurements between the 2 therapies. Patients lost 3 lb on DTE treatment (172.9 ± 36.4 lb vs 175.7 ± 37.7 lb, P < .001). At the end of the study, 34 patients (48.6%) preferred DTE, 13 (18.6%) preferred L-T4, and 23 (32.9%) had no preference. In the subgroup analyses, those patients who preferred DTE lost 4 lb during the DTE treatment, and their subjective symptoms were significantly better while taking DTE as measured by the general health questionnaire-12 and thyroid symptom questionnaire (P < .001 for both). Five variables were predictors of preference for DTE. Conclusion: DTE therapy did not result in a significant improvement in quality of life; however, DTE caused modest weight loss and nearly half (48.6%) of the study patients expressed preference for DTEover L-T4.DTEtherapymaybe relevant forsomehypothyroid patients.