Context: Caloric restriction (CR) retards aging in mammals. It has been hypothesized that a reduction in T3 hormone may increase life span by conserving energy and reducing free-radical production. Objective: The objective of the study was to assess the relationship between long-term CR with adequate protein and micronutrient intake on thyroid function in healthy lean weight-stable adult men and women. Design, Setting, and Participants: In this study, serum thyroid hormones were evaluated in 28 men and women (mean age, 52 ± 12 yr) consuming a CR diet for 3-15 yr (6 ± 3 yr), 28 age- and sex-matched sedentary (WD), and 28 body fat-matched exercising (EX) subjects who were eating Western diets. Main Outcome Measures: Serum total and free T 4, total and free T3, reverse T3, and TSH concentrations were the main outcome measures. Results: Energy intake was lower in the CR group (1779 ± 355 kcal/d) than the WD (2433 ± 502 kcal/d) and EX (2811 ± 711 kcal/d) groups (P < 0.001). Serum T 3 concentration was lower in the CR group than the WD and EX groups (73.6 ± 22 vs. 91.0 ± 13 vs. 94.3 ± 17 ng/dl, respectively) (P ≤ 0.001), whereas serum total and free T4, reverse T 3, and TSH concentrations were similar among groups. Conclusions: Long-term CR with adequate protein and micronutrient intake in lean and weight-stable healthy humans is associated with a sustained reduction in serum T3 concentration, similar to that found in CR rodents and monkeys. This effect is likely due to CR itself, rather than to a decrease in body fat mass, and could be involved in slowing the rate of aging.