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We investigated whether variants in the serotonin transporter gene (SLC6A4) influence smoking cessation rates using antidepressant therapy (i.e. bupropion and nortriptyline).Pharmacogenetic (secondary) analysis of a randomized, placebo-controlled efficacy trial of bupropion and nortriptyline for smoking cessation.Single-centre study, Maastricht University, the Netherlands.A total of 214 of 255 (84%) current daily smokers participating in a randomized controlled efficacy trial.Subjects were genotyped for three functional variants in SLC6A4 (5-HTTLPR, STin2, rs25531). Primary outcome measures were prolonged abstinence from weeks 4–12, 4–26 and 4–52. Secondary outcome measures included 7-day point prevalence abstinence at weeks 4, 12, 26 and 52.Carriers of the 5-HTTLPR high-activity L-variant had higher prolonged cessation rates with bupropion than placebo [odds ratio (OR) = 1.44, 95% confidence interval (CI) = 1.01–2.05, P = 0.04]. Combining the three variants resulted in increased prolonged cessation rates for both bupropion and nortriptyline among carriers of four to five high-activity variants (bupropion: OR = 2.00, 95% CI = 1.21–3.29, P = 0.01; nortriptyline: OR = 1.91, 95% CI = 1.02–3.56, P = 0.04). Similar results were found for point prevalence abstinence.Bupropion and nortriptyline seem to be more effective in smoking cessation among SLC6A4 high-activity variant carriers, probably by blocking the increased serotonin transporter activity, thereby increasing serotonin levels. Prospective studies have to assess if this can improve cessation rates when treatment is targeted at individuals based on their genotypes.