Serum amyloid A (SAA) proteins are a group of phylogenetically conserved acute-phase reactants. Evidence is presented here for the existence of four genetic loci for the human serum amyloid A (SAA) genes. The first locus was defined by three contiguous lambda clones spanning approximately 30 kb which contained a single SAA gene encoding apoSAA1 beta. Allelic variants were isolated at the second locus: a novel clone encoding apoSAA2 alpha was distinguished from SAA2 beta (previously known as SAAg9, Ref.1) by a His/Arg polymorphism at residue 71.SAA1 and SAA2 found in the high density lipoprotein fraction of acute-phase plasma were approximately 90% homologous at the nucleotide level. Homology in the 5' flanking regions was reflected functionally with similar transcriptional responses to inflammatory cytokines in transfected hepatoma cells. A further novel gene, SAA4, was isolated from a cosmid library and mapped 10 kb downstream of SAA2. The locus defining SAA3 has been described elsewhere. Polymorphisms were detected at both SAA1 and SAA2 loci by Southern analysis and the entire SAA region mapped to discrete fragments by pulsed field analysis. The four genes account for all the hybridizing bands present on Southern analyses in a Caucasian population.