Metabolic responses during a very-low-calorie diet, composed of 50 per cent glucose and 50 per cent protein, were studied in 18 grossly obese subjects (relative weights 131-205 per cent) for 28 d. During the last 14 d (period 2) eight subjects (Gp B) served as controls, while the other ten subjects (Gp A) in the low T3 state were treated with triiodothyronine supplementation (50 micrograms, 3 times daily). During the first 14 d (period 1) a low T3-high rT3 state developed; there was an inverse relationship between the absolute fall of the plasma T3 concentrations and the cumulative negative nitrogen balance as well as the beta-hydroxybutyrate (BOHB) acid concentrations during the semi-starvation period, pointing to a protein and fuel sparing effect of the low T3 state. Weight loss in the semi-starvation period was equal in both groups; during T3 treatment the rate of weight loss was statistically significant (Gp A 6.1 +/- 0.3 kg vs Gp B 4.2 +/- 0.2 kg, P less than 0.001). In the control group there was a sustained nitrogen balance after three weeks; in Gp A the nitrogen losses increased markedly during T3 treatment. Compared to the control group, on average a further 45.4 g extra nitrogen were lost, equivalent to 1.4 kg fat free tissue. Thus, 74 per cent of the extra weight loss in the T3 treated group could be accounted for by loss of fat free tissue. During the T3 treatment period no detectable changes occurred regarding plasma triglycerides and plasma free fatty acids (FFA) concentrations; the plasma BOHB acid concentrations decreased significantly as compared to the control group. Plasma glucose concentrations and the immunoreactive insulin (IRI)/glucose ratio increased in Gp A in the T3 treatment period, reflecting a state of insulin resistance with regard to glucose utilization. Our results warrant the conclusion that there appears to be no place for T3 as an adjunct to dieting, as it enhances mostly body protein loss and only to a small extent loss of body fat.