Introduction: The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) that began in Wuhan (China), that spread rapidly worldwide, seriously affecting the population leading to a public health emergency declared by the World Health Organization. It is unknown how SARS-CoV-2 infection can affect thyroid function. In this study, we describe the characteristics of an unusual analytical interference that may explain the false detection of hypothyroidism in patients with SARS-CoV-2 infection. This is the first time that a phenomenon of this nature has been described in patients with COVID-19 and underlying thyroid dysfunction. Material and Methods: Observational study of patients admitted for severe COVID-19 infection and underlying thyroid disease. Results: TSH levels presented an atypical pattern different from that of Euthyroid Sick Syndrome (ESS), confirmed by the lack of response to substitution treatment. We develop different studies to confirm or eliminate potential interferences, being diagnosed of a possible macro-TSH. Conclusion: It is important to consider that in patients with COVID-19 and high concentrations of TSH and thyroid hormones within reference ranges with lack of response to treatment, one of the possible causes to consider is the presence of macro-TSH. The presence of macro-TSH interference in COVID-19 patients requires extreme precautions to avoid errors in diagnosis or treatment (replacement dose adjustment) in patients with hypothyroidism secondary to an underlying disease.