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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.Our objective was to investigate the effectiveness of DTE compared with L-T4 in hypothyroid patients.We conducted a randomized, double-blind, crossover study at a tertiary care center.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.Patients were randomized to either DTE or L-T4 for 16 weeks and then crossed over for the same duration.Biochemical and neurocognitive tests at baseline and at the end of each treatment period were evaluated.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.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 DTE over L-T4. DTE therapy may be relevant for some hypothyroid patients.