An LPS-stimulated, human monocyte cDNA library was screened for stimulation-specific clones. One clone (pcD-1214) contained a 1.9-kb pair insert that hybridized to a 2,000-nucleotide mRNA expressed by peripheral blood monocytes, the histiocytic lymphoma cell line U937, and umbilical cord endothelial cells. The 415-amino-acid precursor polypeptide predicted from the cDNA (46,596 molecular weight) has a putative 22-residue signal peptide and approximately 35% homology with members of the serine protease inhibitor (Serpin) superfamily. On the basis of amino acid homology and alignment of COOH-terminal residues within the Serpin-reactive center, the clone pcD-1214 was identified as coding for an Arg-Serpin. Southern blot analysis of human-mouse somatic cell hybrid DNA locates the Arg-Serpin gene on human chromosome 18. A perfect match between amino acid residues 347-376 in this Arg-Serpin and the published sequence of a 30-residue, tryptic peptide from the COOH-terminus of a monocyte plasminogen activator-inhibitor (PAI-2), strongly suggests that the Arg-Serpin encoded by pcD-1214 is PAI-2.