Although T3 exerts major regulatory actions in both animals and humans, most clinical studies of T3 administration have been relatively short term. The present study examined the effects of more than 2 months (63 days) of low dose T3 treatment on nitrogen balance, body composition, 24-h energy expenditure (EE), and protein turnover in seven healthy men studied at an in-patient metabolic unit. Subjects were also randomly assigned to either high or low fat diets to determine the effects of diet composition. T3 treatment produced significant losses in both lean mass (1.5 +/- 0.3 kg) and fat mass (2.7 +/- 0.4 kg) by 6 weeks, with similar reductions in both at 9 weeks. The high fat diet somewhat attenuated the loss of body fat. Nitrogen balance was significantly negative for the first 3 weeks of T3 treatment, but tended to return to baseline thereafter. There were no significant effects of treatment on protein turnover at 9 weeks, although there was a slight increase in leucine oxidation (P = 0.07). Despite the apparent adaptation in nitrogen balance, total 24-h EE and sleeping EE were significantly increased at 9 weeks. We conclude that although healthy men are able to adapt to mild hyperthyroidism in terms of nitrogen balance, they exhibit significant and persistent changes in fat and fat-free mass as well as energy balance.