We have determined the exon/intron organization of the human lipopolysaccharide binding protein (LBP) and bactericidal permeability increasing protein (BPI) genes. The LBP gene spans approximately 28.5 kb and is composed of 14 exons while the 31.5-kb-long BPI gene is composed of 15 exons. Comparison of the genomic organization of the LBP and BPI genes together with the genomic structures of the PLTP (phospholipid transfer protein) and CETP (cholesteryl ester transfer protein) genes, which all together constitute a gene family of functionally related proteins, revealed high homology with a remarkable conservation of exon/intron transitions. The exon/intron junctions of the LBP, BPI, and PLTP genes are almost identical, with most of the exons being of the same size. In addition, functional domains are conserved in these proteins. The C-terminal octapeptide important for CETP anchoring in lipoprotein particles is also present in LBP, BPI, and PLTP. The LPS binding motif in exons 3 and 4 has been retained in LBP and BPI. Our results indicate that the LBP, BPI, and PLTP genes, and probably the CETP gene, may have evolved from a common primordial gene and may share similar functional properties.