BACKGROUND Individual differences in subjective responses to stimulant drugs such as amphetamine may influence risk of abuse as well as clinical-treatment response to these drugs. Because the effects of amphetamine are mediated in part by the norepinephrine transporter (SLC6A2), we examined interindividual differences in mood response to amphetamine in relation to SLC6A2 gene polymorphisms. METHODS Ninety-nine healthy volunteers participated in three sessions in which they randomly received either placebo or D-amphetamine (10 mg or 20 mg) under double-blind conditions. Every subject completed self-report measures on subjective effects (Profile of Mood States). Afterward, all individuals were genotyped for eight SLC6A2 gene polymorphisms. Individual genotypes and haplotypes were investigated. RESULTS The intronic 36001C/C (rs47958) genotype was associated with increases in positive mood and elation after 20 mg of D-amphetamine. Positive mood and elation levels were also found to be associated with the haplotype GCC formed from 28257G/C (rs36017), 28323C/T (rs2270935), and 36001A/C (rs47958). These findings remained significant after adjustment for multiple testing. CONCLUSIONS Polymorphisms in the SLC6A2 gene were associated with mood responses to D-amphetamine. If confirmed, this observation may contribute to a better understanding of interindividual variations in the clinical response to amphetamine and in the risk of becoming addicted to amphetamine.