Methadone is widely prescribed (about 215'000 opioid dependent patients and >275'000 patients treated for pain in the US, and about 150'000 subjects in methadone maintenance therapy in the EU). Methadone inhibits the cardiac potassium channel hERG and can cause a prolonged QT interval, with several described cases of torsades de pointes and sudden deaths. Methadone is chiral but its therapeutic (opioid) activity is mainly due to (R)-methadone. Using whole-cell patch-clamp experiments using cells expressing hERG, we showed, that (S)-methadone blocked the hERG current 3.5-fold more potently than (R)-methadone (IC50s at 37°C: 2 and 7µM; Eap et al., Clin Pharmacol Ther 81:719-28, 2007). In addition, as CYP2B6 slow metabolizer (SM) status results in a reduced ability to metabolize (S)-methadone (Crettol et al. Clin Pharmacol Ther, 78(6) :593-604, 2005), electrocardiograms, CYP2B6 genotypes, and (R)- and (S)-methadone plasma concentrations were obtained for 179 patients receiving (R,S)-methadone (Eap et al., Clin Pharmacol Ther 81:719-28, 2007). The mean heart-rate-corrected QT (QTc) was higher in CYP2B6 SMs (*6/*6 genotype; 43925ms; n=11) than in extensive metabolizers (non *6/*6; 42125ms; n=168; P=0.017). CYP2B6 SM status was associated with an increased risk of prolonged QTc (odds ratio=4.5, 95% confidence interval=1.2-17.7; P=0.03). This study reports a stereoselectivity in the hERG channel blockade and a potential safer cardiac profile of (R)-methadone. In addition, it reports the first genetic factor implicated in methadone metabolism that may increase the risk of cardiac arrhythmias and sudden death. The prescription of the pure enantiomer would therefore reduce the risk of cardiac toxicity and sudden death in the very large number of patients treated with methadone worldwide. Interestingly, our studies also suggests that stereoselectivity in the hERG current blockade should be more often considered in the field of drug-induced prolonged QT interval which, in addition to methadone, could lead to the finding of other, safer drugs.