The aim of the case study was to report the successful use of intramuscular levothyroxine (L-T 4 ) in two patients with profound oral L-T 4 malabsorption. We present two cases of patients who remained hypothyroid despite very high oral doses of L-T 4 . In both cases, poor L-T 4 absorption was documented with an absorption study. Intramuscular L-T 4 injections were initiated in both cases and doses were titrated to achieve normalization of thyroid stimulating hormone (TSH) and free thyroxine (free T 4 ). Additionally, after achieving euthyroidism for a period of time, each patient was able to successfully transit back to oral administration of L-T 4 . Synthetic oral L-T 4 is the drug of choice for replacement therapy in patients with hypothyroidism. Whenever euthyroidism cannot be achieved despite escalating L-T 4 doses, the presence of interfering factors must be considered. These factors include low patient compliance or reduced L-T 4 absorption due to other dietary factors, concomitant medication use or gastrointestinal disease. Furthermore, severe hypothyroidism itself may impair absorption, presumably due to edema of the small bowel mucosa. Parenteral L-T 4 has been shown to be an effective method of replacing thyroid hormone in those patients with apparent thyroid hormone malabsorption. However, there is no consensus or guidelines available to aid physicians in the use of parenteral L-T 4 . In patients with hypothyroidism despite large doses of levothyroxine, physicians should consider thyroid malabsorption once compliance and interfering medicines have been ruled out. In these patients, if no correctable interfering factor is identified, intramuscular replacement appears to be an effective alternative.