OBJECTIVE: Patients are increasingly using and requesting LT4/LT3 combination treatment for persistent hypothyroid symptoms, but the efficacy and side effects of long-term therapy remain largely unexplored. This study aimed to describe the patient group experiencing a long-lasting impact of LT4/LT3 and evaluate their Quality of Life (QoL) and hypothyroid symptoms. METHOD: We performed a cross-sectional study of 66 hypothyroid patients who had previously initiated LT4/LT3 combination therapy. The patients were grouped by current treatment into patients still receiving LT4/LT3 treatment (T3 responders) and patients who had discontinued LT3 treatment due to lack of effect (T3 non-responders). ThyPRO was used to evaluate QoL, and a validated symptom score was used to assess hypothyroid symptoms. The paper describes a real-life study that depicts unsatisfied patients as they are met in an outpatient clinic. RESULTS: The participants had a median age of 56 and had initiated LT4/LT3 combination therapy 5.4 years ago. Fifty-four patients still received LT4/LT3 therapy, and 12 patients had discontinued LT3 treatment due to lack of effect. Patients in the T3 responder group experienced a QoL comparable to the background population. Surprisingly, symptom scores in the T3 responder group were at the same levels as seen in Danish females with overt hypothyroidism. TSH in the T3 responder group were less than 0.4 mU/L in 38% of patients, indicating overtreatment. CONCLUSION: LT4/LT3 treatment was well tolerated with no side effects and with high QoL, but patients still experienced many symptoms.