While neuropsychological deficits are evident among methamphetamine (meth) addicts, they are often unrelated to meth exposure parameters such as lifetime consumption and length of abstinence. The notion that some meth users develop neuropsychological impairments while others with similar drug exposure do not, suggests that there may be individual differences in vulnerability to the neurotoxic effects of meth. One source of differential vulnerability could come from genotypic variability in metabolic clearance of meth, dependent on the activity of cytochrome P450-2D6 (CYP2D6). We compared neuropsychological performance in 52 individuals with a history of meth dependence according with their CYP2D6 phenotype. All were free of HIV or hepatitis C infection and did not meet dependence criteria for other substances. Extensive metabolizers showed worse overall neuropsychological performance and were three times as likely to be cognitively impaired as intermediate/poor metabolizers. Groups did not differ in their demographic or meth use characteristics, nor did they evidence differences in mood disorder or other substance use. This preliminary study is the first to suggest that efficient meth metabolism is associated with worse neurocognitive outcomes in humans, and implicates the products of oxidative metabolism of meth as a possible source of brain injury.