Oral opiates (e.g. codeine, oxycodone, and hydrocodone) are metabolized by cytochrome CYP2D6 to metabolites of increased activity (e.g. morphine, oxymorphone and hydromorphone). CYP2D6 is genetically polymorphic, 4-10% of Caucasians lack CYP2D6 activity (poor metabolizers) due to inheritance of two non-functional alleles. We tested whether the failure to activate oral opiates was a protection factor in opiate dependence by genotyping (CYP2D6*3 and CYP2D6*4 defective mutant alleles) caucasians who met or didn't meet DSM criteria for oral opiate dependence. In opiate (+/- smoking) dependent subjects we found no poor metabolizers. In contrast, the poor metabolizer frequency in never-dependent control and multi-drug dependent comparison groups was 4% and 6.5%, respectively. This under-representation of poor metabolizers (Fisher's exact test, p < or = 0.05) in people dependent on oral opiates suggests that the CYP2D6 defective genotype is a pharmacogenetic protection factor for oral opiate dependence (estimated odds ratio > 7). This is the first investigation and demonstration of differences in genetically determined P450 metabolism influencing risk for substance dependence and we suggest that these differences may influence the risk for dependence of other substrate drugs, and may occur with other genetically variable P450s.