We have isolated a full-length human liver cDNA clone specifying the nuclear-encoded subunit IV of the human mitochondrial respiratory chain enzyme, cytochrome c oxidase (COX; EC 1.9.3.1). The human cDNA clone is highly homologous to its bovine counterpart in the coding regions for both the mature polypeptide and the presequence, and the gene is evolving more slowly than that of any of the three mitochondrially encoded COX subunit genes. We find no preliminary evidence for tissue-specific isoforms of COX subunit IV, as Northern analysis of muscle, liver, and HeLa cell RNA shows an identically sized transcript in each cell type.