The biogenic amine histamine is an important modulator of numerous physiological processes, including neurotransmittance, gastric acid secretion and smooth muscle tone. The biosynthesis of histamine is catalyzed by the enzyme, L-histidine decarboxylase (HDC). We have previously reported the cloning and sequence of the cDNA encoding rat HDC. Utilizing the rat HDC cDNA as probe the full-length cDNA encoding human HDC was identified and characterized. The encoded protein of 662 amino acid residues has a molecular weight of 74,148. Homology comparisons of the deduced amino acid sequence with rat HDC and dopa decarboxylases from three species have revealed highly related regions. These comparisons have identified domains of amino acid decarboxylases that are highly conserved and are likely important for enzyme-substrate interaction. A dissimilar region in human and rat HDC primary translated protein near the C-terminus would appear not to be important for catalysis and may be removed by proteolysis. This processing phenomenon could be in part responsible for regulation of HDC activity. The human HDC cDNA was also utilized to map the chromosomal location of the human HDC gene locus (HDC). Analysis of human-rodent cell hybrids revealed that the HDC gene segregates with Chromosome 15. No restriction length polymorphisms in the human population were detected after cleavage of the DNAs with 12 restriction endonucleases.