The debrisoquine polymorphism is a common genetic defect that results in deficient oxidation of debrisoquine and numerous other drugs. These compounds are metabolized by a form of cytochrome P450, designated CYP2D6. Some 5%-10% of Caucasians are unable to metabolize debrisoquine, because of mutant alleles of CYP2D6. A CYP2D6 allele was isolated from leukocyte DNA of an individual who was deficient in debrisoquine metabolism. The gene was completely sequenced, including 725 bp of upstream and 400 bp of downstream DNA. Several base changes were uncovered within the exons, resulting in four amino acid differences between the mutant and wild-type allele. Most important, a single base change G1934----A at the junction of the third intron and four exon would result in an incorrectly spliced primary transcript and in an mRNA having a single base deletion. This deletion presumably disrupts the mRNA reading frame, resulting in a truncated protein. These data establish unequivocally that the debrisoquine polymorphism is the result of mutant CYP2D6 alleles and provide a framework to design a genetic test for this drug oxidation deficiency. A defective CYP2D7 allele was also isolated and completely sequenced, providing evidence that gene conversions have occurred between CYP2D6 and CYP2D7.