The influence of thyroid hormone (T₃) on respiration is partly mediated via its effect on the cytochrome c oxidase (COX) enzyme, a multi-subunit complex within the mitochondrial respiratory chain. We compared the expression of COX subunits I, III, Vb, and VIc, and thyroid receptors (TR)1 and TR1, to functional changes in COX activity in tissues that possess high oxidative capacities. In response to 5 days of T₃ treatment, TR1 increased 1.6-fold in liver while TR1 remained unchanged. T₃ also induced concomitant increases in the protein and mRNA expression of nuclear-encoded subunit COXVb in liver, matched by a 1.3-fold increase in binding to a putative thyroid response element (TRE) within the COXVb promoter in liver, suggesting transcriptional regulation. In contrast, T₃ had no effect on COXVb expression in heart. T₃ produced a significant increase in COXIII mRNA in liver, but decreased COXIII mRNA in heart. These changes were matched by parallel alterations in mitochondrial transcription factor A (Tfam) expression in both tissues. In contrast, COXI protein increased in both liver and heart by 1.7- and 1.5-fold (p<0.05) respectively. These changes in COXI closely paralleled the T₃-induced increases in COX activity observed in both of these tissues. In the liver, T₃ induced a coordinated increase in the expression of the nuclear (COXVb) and mitochondrial (COXI) genomes at the protein level. However, in the heart, the main effect of T₃ was restricted to the expression of mitochondrial DNA (mtDNA) subunits. Thus, our data suggest that T₃ regulates the expression of COX subunits by both transcriptional and post-transcriptional mechanisms. The nature of this regulation differs between tissues possessing a high mitochondrial content, like liver and heart.