OBJECTIVE The synthetic thyroid hormone levothyroxine-sodium (LT4) is still the treatment of choice to replace thyroid hormone deficiency in hypothyroidism, and for adjuvant treatment of euthyroid goiter. A change of LT4 preparations during treatment may lead to major changes of thyroid hormone levels. In this study, we compared the bioavailability of two LT4 preparations, L-Thyroxin Henning 100 and Eferox 100. METHODS In a double-blind trial, 60 euthyroid volunteers were randomly assigned to two treatment groups. Over a period of 2 weeks, each group received 0.1 mg/d of the different preparations according to a "crossover design". To monitor the efficacy of the different drugs, baseline serum thyrotropin (TSH) and free thyroxine (fT4) levels were measured with the help of immunoenzyme tests. RESULTS Compared to Eferox, L-Thyroxin Henning led to continuously higher fT4 levels (p = 0.0004). The area under the concentration-time curve (AUC) of fT4 also confirmed this highly significant difference. With respect to the influencing factors, a higher bioavailability in men compared to women (p = 0.004) was noted. Also, the increase of body weight was related to a lower bioavailability (p = 0.002). Regarding the baseline TSH serum levels, a reduction of 70% in the L-Thyroxin Henning group versus only 56% in the Eferox group was noted after a period of 14 days. Clinical symptoms of hyperthyroidism were not observed in the volunteers under both substances. CONCLUSIONS In this study, L-Thyroxin Henning 100 showed a significantly higher bioavailability than Eferox 100 (p = 0.001). According to these findings, we do recommend regular measurements of serum TSH and fT4 levels when changing LT4 preparations of different brands, to cope with metabolic decompensation by using a new LT4 dosage.