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Polymorphisms in the dopamine D2 receptor (32806DRD2 C/T and 22316DRD2 A/G) and in dopamine beta hydroxylase (1368DBH A/G) have been implicated in modulation of smoking and other reward-seeking behaviours. We hypothesized that these alleles would predict the outcome of nicotine patch therapy for smoking cessation. In 1991–93, we performed a randomized controlled trial of the nicotine patch on 1686 heavy smokers (≥ 15 cigarettes/day). In 1999–2000, we contacted 1532 of the 1612 subjects still available; 767 (50%) completed a questionnaire and gave a blood sample. In the 755 cases in which DNA was successfully genotyped, we examined associations between the polymorphisms in DRD2 and DBH, and smoking cessation. At 1 week, the patch was more effective for smokers with 32806DRD2 CT/TT genotype [patch/placebo odds ratio (OR) 2.8, 95% confidence interval (CI) 1.7–4.6] than with CC (OR 1.4, 0.9–2.1; P for difference in ORs 0.04). Smokers with both 32806DRD2 CT/TT and 1368DBH GA/AA genotypes had an OR of 3.6 (2.0–6.5) compared to 1.4 (1.0–2.1) for others (P = 0.01). At 12 weeks, the ORs for these genotypic groups were 3.6 (1.7–7.8) and 1.4 (0.9–2.3), respectively (P = 0.04). There was no association between patch effectiveness and 22316DRD2 exon 8. Short-term effectiveness of the nicotine patch may be related to dopamine beta-hydroxylase and dopamine D2 receptor genotype. Our results support the need for further investigation into personalized therapies for smoking cessation based on individual genotype.