We examined a possible mechanistic interaction between leptin and thyroid hormones in rats with hypothyroidism induced by thyroidectomy (TX) and propylthiouracil administration. In study 1, the TX rats were treated by vehicle (V, n = 9) or by recombinant murine leptin (L, 0.3 mg · kg¹ · day¹, n = 9) or were pair-fed (PF, n = 9) against L. In study 2, the TX rats were all given 3,3'5'-triiodo-L-thyronine (T₃) replacement (T, 5 µg · kg¹ · day¹) to correct hypothyroidism. They were then subdivided into three groups, namely, vehicle (T+V, n = 9), leptin (T+L, n = 10), and pair-feeding (T+PF, n = 9), similar to study 1 except for T₃ (T). Reduced food consumption and weight gain in the TX rats were reversed by T₃ replacement. Leptin suppressed food intake in the TX rats regardless of T₃ replacement. O₂ consumption (O₂) and CO₂ production (CO₂) were reduced in TX rats (P < 0.05 vs. normal) but were normalized by either T₃ or leptin treatment. T+L additively increased O₂ and CO₂ (P < 0.05 vs. TX, T₃, and L). The respiratory exchange ratio was unaltered in TX rats, with and without T₃, but was significantly reduced by L or T+L treatments. These results indicate that the metabolic actions of leptin are not dependent on a normal thyroid status and that the effects of leptin and T₃ on oxidative metabolism are additive.