A complementary DNA for the very-low-density lipoprotein receptor (VLDLR) that codes for a protein of 873 amino acids was cloned from a human heart cDNA library. The mature protein of 846 amino acids, preceded by a 27-residue signal peptide, shares 97% amino acid sequence identity with the rabbit VLDLR. Like the low-density lipoprotein receptor, the VLDLR contains five different domains, all of which are highly conserved between human and rabbit. A tetrapeptide NPVY that potentially serves as a signal for clustering of the VLDLR on coated pits is present in the cytoplasmic domain, which is 100% conserved between human and rabbit. We localized the VLDLR gene to chromosome 9p24 by fluorescence in situ hybridization using the cloned cDNA as hybridization probe. The high amino acid sequence homology of the VLDLR between two mammalian species suggests that the receptor plays a fundamental role in lipoprotein metabolism and that energy metabolism mediated by triglyceride utilization may be an evolutionarily highly conserved mechanism.