This study tested the hypothesis that low-dose 3,5,3'-triiodothyronine (T₃) administration during prolonged bed rest improves the ground-based model of spaceflight. Nine men (36.4 ± 1.3 yr) and five women (34.2 ± 2.1 yr) were studied. After a 5-day inpatient baseline period, subjects were placed at total bed rest with 6° head-down tilt for 28 days followed by 5-day recovery. Fifty micrograms per day of T₃ (n = 8) or placebo (n = 6) were given during bed rest. Serum T₃ concentrations increased twofold, whereas thyroid-stimulating hormone was suppressed in treated subjects. T₃-treated subjects showed significantly greater negative nitrogen balance and lost more weight (P = 0.02) and lean mass (P < 0.0001) than placebo subjects. Protein breakdown (whole body [¹³C]leucine kinetics) increased 31% in the T₃ group but only 8% in the placebo group. T₃-treated women experienced greater changes in leucine turnover than men, despite equivalent weight loss. Insulin sensitivity fell by 50% during bed rest in all subjects (P = 0.005), but growth hormone release and insulin release were largely unaffected. In conclusion, addition of low-dose T₃ to the bed rest model of muscle unloading improves the ground-based simulation of spaceflight and unmasks several important gender differences.