Central dopaminergic reward pathways give rise to dependence and are activated by nicotine. Allelic variants in genes involved in dopamine metabolism may therefore influence the amount of tobacco consumed by smokers. We developed assays for polymorphisms in dopamine beta-hydroxylase (DBH), monoamine oxidase (MAO) and catechol O-methyl transferase (COMT) using the polymerase chain reaction with sequence specific primers (PCR-SSP). We then typed 225 cigarette smokers to assess whether genotype was related to the number of cigarettes smoked a day. Smokers with DBH 1368 GG genotype smoked fewer cigarettes than those with GA/AA [mean difference -2.9 cigarettes, 95% confidence interval (CI) -5.5, -0.4; P = 0.022]. The effect reached statistical significance in women (-3.8, 95% CI -6.4, -1.0, P = 0.007) but not in men (-1.5, 95% CI -6.0, 3.0, P = 0.498). Overall, the effect was greater when analysis was confined to Caucasians (-3.8, 95% CI -6.6, -1.1, P = 0.007). Smokers with MAO-A 1460 TT/TO smoked more cigarettes than those with CC/CT/CO (2.9, 95% CI 0.6, 5.1, P = 0.013). Within each sex group, the trend was similar but not statistically significant (difference for men 2.9, 95% CI -1.0, 6.7; for women 2.0, 95% CI -0.7, 4.8). The effect of the allele was greater in smokers with a high body mass index (> 26) (difference 5.1, 95% CI 1.4, 8.8, P = 0.008). More heavy smokers (> 20 a day) had the DBH 1368A allele when compared to light smokers (< 10 a day). (Relative risk 2.3, 95% CI 1.1, 5.0, P = 0.024.) The trend for increasing prevalence of the DBH A allele in heavy smokers was greater when analysis was restricted to Caucasians (relative risk 3.2, 95% CI 1.3, 8.2, P = 0.004). Conversely, heavy smokers were less likely to have the MAO-A 1460C allele (relative risk 0.3, 95% CI 0.1, 0.7, P = 0.012). Variations in DBH and MAO predict whether a person is a heavy smoker and how many cigarettes they consume. Our results support the view that these enzymes help to determine a smoker's requirement for nicotine and may explain why some people are predisposed to tobacco addiction and why some find it very difficult to stop smoking. This finding has important implications for smoking prevention and offers potential for developing patient-specific therapy for smoking cessation.