High-molecular-weight serine proteinase inhibitors (serpins) regulate a diverse set of intracellular and ex-tracellular processes such as complement activation, fibrinolysis, coagulation, cellular differentiation, tumor suppression, apoptosis, and cell migration. The ovserpins are a subset of the serpin superfamily and are characterized by their high degree of homology to chicken ovalbumin, the lack of N- and C-terminal extensions, the absence of a signal peptide, and a Ser rather than an Asn residue at the penultimate position. Recently, we mapped four members of the family [SCCA1, SCCA2, PAI2, and PI5 (maspin)] to a 300-kb region within 18q21.3. Using a panel of 18q21.3 YAC clones, PCR, and DNA blotting, we mapped two additional ovserpins, cytoplasmic antiproteinase 2 [CAP2 (PI8)] and bone marrow-associated serpin [bomapin (PI10)], to the same region. Three of the serpins, PI8, PI10, and PAI2 mapped to the same YACs, yA27D8 and yA24E4. We estimated that the size of the 18q21.3 serpin cluster spanned ~500 kb and contained at least six setpin genes. The order was cen PI5, SCCA2, SCCA1, PAI2, PI10, PI8-tel. The clustering of serpins at 18q21 provides new opportunities to study coordinate gene regulation and the evolution of gene families.