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-T₄ 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