Core I protein is a nuclear-encoded component of the ubiquinol-cytochrome c reductase complex of the mitochondrial respiratory chain. We have located the gene for the human core I protein in the p21 region of chromosome 3, just upstream of the COL7A1 gene which encodes type VII collagen. The core I gene, which has been sequenced in its entirety, is comprised of 10,417 base pairs, from the major transcription start site to the polyadenylation signal, and contains 13 exons. The predicted polypeptide contains 480 amino acids, of which the first 34 are predicted to constitute a typical mitochondrial leader peptide containing 6 positively charged arginine residues. The predicted human protein shows significant homology with core I protein from Saccharomyces cerevisiae, rather high homology (64% similarity, 46% identity) with the processing enhancing protein, which functions as core I protein in Neurospora crassa, and, surprisingly, highest homology with the small subunit of the mitochondrial processing peptidase of rat (74% similarity, 55% identity). The predicted human sequence is 87% identical to the reported bovine core I sequence predicted from cDNA cloning, up to residue 298, but the two predicted sequences are widely divergent after that point.