Introduction: Some levothyroxine unresponsive individuals with hypothyroidism are prescribed a natural desiccated thyroid (NDT) preparation such as Armour Thyroid^® or ERFA Thyroid^®. These contain a mixture of levothyroxine and liothyronine in a fixed ratio. We evaluated the response to NDT in individuals at a single endocrine centre in terms of how the change from levothyroxine to NDT impacted on their lives in relation to quality of life (QOL) and thyroid symptoms. Methods: The ThyPRO39 (thyroid symptomatology) and EQ-5D-5L-related QoL/EQ5D5L (generic QOL) questionnaires were administered to 31 consecutive patients who had been initiated on NDT, before initiating treatment/6 months later. Results: There were 28 women and 3 men. The dose range of NDT was 60-180 mg daily. Age range was 26-77 years with length of time since diagnosis with hypothyroidism ranging from 2 to 40 years. One person discontinued the NDT because of lack of response; two because of cardiac symptoms. EQ-5D-5L utility increased from a mean (SD) of 0.214 (0.338) at baseline, to 0.606 (0.248) after 6 months; corresponding to a difference of 0.392 (95% CI 0.241-0.542), t = 6.82, P <.001. EQ-VAS scores increased from 33.4 (17.2) to 71.1 (17.5), a difference of 37.7 (95% CI 25.2-50.2), t = −4.9, P <.001. ThyPRO scores showed consistent fall across all domains with the composite QoL-impact Score improving from 68.3 (95% CI 60.9-75.7) to 25.2 (95% CI 18.7-31.7), a difference of 43.1 (95% CI 33-53.2) (t = 5.6, P <.001). Conclusion: Significant symptomatic benefit and improvement in QOL was experienced by people with a history of levothyroxine unresponsive hypothyroidism treated with NDT, suggesting the need for further evaluation of NDT in this context.