There is a genetic polymorphism in humans in the metabolism of S-mephenytoin which has been suggested to be mediated by either CYP2C18 or CYP2C9. We have isolated genomic clones for CYP2C9 and CYP2C18 from the liver of an individual phenotyped in vitro as an extensive metabolizer of S-mephenytoin. Analysis of the genes reveals nine coding exons spanning approximately 55 kb. The intron-exon organization was similar to that of other members of the CYP2C subfamily. Analysis of 2200 bp of 5' upstream sequence for CYP2C9 and 1300 bp 5' upstream sequence for CYP2C18 reveals canonical TATA boxes situated 57 bp upstream from the first codon, multiple consensus sequences for glucocorticoid regulatory elements, and identification of a 15 base sequence with high homology to a 5'-flanking sequence responsible for barbiturate-inducible expression of P450BM-3 in Bacillus megaterium. The upstream region for CYP2C9 was highly homologous (75%) to that of human CYP2C8 through most of the 2200 bp sequenced, but the upstream region of CYP2C18 was similar to CYP2C8 and CYP2C9 for only the first 200 bases. The availability of the sequences of the upstream regions and intron-exon junctions of CYP2C9 and CYP2C18 will allow future analysis of these genes in humans which differ in their ability to metabolize S-mephenytoin and other drugs.