Because of the predominance of 15-lipoxygenase activity in airway epithelium and because of the known biological activities of 15-lipoxygenase metabolites, we have initiated detailed studies of this enzyme. The enzyme was isolated to homogeneity from eosinophil-enriched leukocytes. Using oligonucleotide probes, we isolated a full-length cDNA encoding 15-lipoxygenase from a human reticulocyte cDNA library. The clone is immunologically related to leukocyte 15-lipoxygenase and has been expressed in mammalian cells. Demonstration of active catalytic function is further proof of the authenticity of the isolated clone. The predicted amino acid structure shares significant sequence similarity with other lipoxygenases in certain regions. This extends our earlier observation that the lipoxygenases form a family of enzymes. Furthermore, the conservation of amino acid residues in select regions suggests a role in enzymatic activity. The availability of a clone for 15-lipoxygenase should prove useful in studying the structure and function of the enzyme, the regulation of 15-lipoxygenase gene expression, and the comparison of 15-lipoxygenases from various cells and tissues.