In euthyroid hyperthyroxinemia high levels of thyroxine (T4) may be either transient or persistent, associated with high, normal, or low levels of tri-iodothyronine (T3). Euthyroid hyperthyroxinemia may occur: as a response to abnormal plasma binding (thyroxine binding globulin, albumin, prealbumin, or autoantibodies), because of hormone resistance, after exposure to drugs such as amiodarone, cholecystographic contrast agents, or propranolol, during acute psychiatric illness or stress, and in hyperemesis gravidarum. In some instances the cause of persistent hyperthyroxinemia still remains obscure. No single investigation (including free hormone measurement and the response of thyrotropin to its releasing hormone) can distinguish all of these entities from true hyperthyroidism. Hence, re-evaluation in cases of diagnostic uncertainty should begin with clinical reassessment. Techniques are now available to identify easily some causes of euthyroid hyperthyroxinemia, allowing us to recognise patients and relatives who are at risk of inappropriate treatment. Because measurement of serum T4 remains the key investigation for diagnosis of thyroid dysfunction, it is important to appreciate the full range of conditions that compromise its specificity.