Standard treatment of primary hypothyroidism is with thyroxine, with the aim of relieving symptoms and bringing the serum TSH (thyroid-stimulating hormone) concentration to within the reference range. Recent research suggests that in some patients symptoms of hypothyroidism persist despite standard thyroxine replacement therapy. The optimal treatment of these patients is not known. Adjusting the thyroxine dose until the serum TSH concentration is in the lower part of the reference range (eg, 0.3-2.0 mU/L) may be beneficial. Animal studies and a single small clinical trial suggest that a combination of thyroxine and T3 (triiodothyronine), rather than thyroxine alone, may be required for optimal thyroid replacement therapy. Further research is needed to determine why some patients appear to have a suboptimal response to thyroxine, and whether combined thyroxine/T3 treatment is preferable to thyroxine alone in these patients.