We present a 49-year-old patient suffering from hypothyroidism (thyrotropin [TSH], 20-80 mU/L) refractory to oral levothyroxine (LT(4)) substitution after total thyroidectomy and radioiodine therapy for papillary thyroid cancer. Extensive, repetitive work-up excluded small bowel, liver, and pancreatic disease and drug interactions. Triiodothyronine/thyroxine (T(3)/T(4)) antibodies were negative and reverse T(3) levels were normal. Supervised absorption tests of several LT(4) preparations in increasing dosages (250-1500 microg/d) confirmed an insufficient rise in serum T(4) levels following oral drug administration. Thus, intravenous LT(4) application (5 times per week) was commenced to restore at least normal range TSH levels. Repetition of absorption tests 1 year later, after a documented period of more than 3 months of stable euthyroidism, showed a considerable improvement of intestinal LT(4) uptake. Subsequently, the patient was managed on large doses of oral LT(4) (1500-2100 microg/d) alone, but this was found to be insufficient so that continuous intravenous LT(4) was administered via a morphine pump device to ultimately achieve stable euthyroidism. Of note, at 4-year follow-up there was no evidence of recurrent or metastasized papillary thyroid cancer. The reason for the disturbed intestinal LT(4) absorption in this patient remains unresolved. However, we would like to suggest the possibility of a specific intestinal uptake deficit, which will only become apparent in the case of previous thyroid ablation.