An inadequate response to levothyroxine treatment in a patient with hypothyroidism suggests lack of intake, lack of absorption, nephrotic syndrome, thyroid hormone resistance among other reasons. We present the case of two women with hypothyroidism and a persistently elevated level of TSH, which required increasing the dose of levothyroxine, resulting in a clinical hyperthyroidism with an abnormally high TSH. A TSH and free T4 follow up was performed during a period of 20 and 10 months respectively, in both situations there was not an adequate response to rising levothyroxine treatment. After ruling out other possible causes that could explain this situation, it was suspected and then confirmed the presence of Macro TSH, which is a biologically inactive complex of TSH and Immunoglobulin G. Therefore, both patients achieved disease stability once controlled by clinical state and free T4 measurements, understanding why THS persited high. We present these interesting cases, because this allows us to remember atypical causes of refractory treatment with levothyroxine, such as the Macro TSH, indispensable to search for the proper management of these patients.