Objectives We attempted to extend a previous finding of an association of COMT genotype with response to nicotine-replacement therapy (NRT), in a larger cohort of treatment-seeking smokers, with greater statistical power to detect possible moderating effects of sex. We also investigated the association of the COMT genotype with withdrawal and mood symptoms, to identify possible mediating mechanisms by which the COMT genotype might influence response to NRT. Methods Participants were eligible if they were aged 18 years or older, and if they smoked 10 cigarettes per day or more; they were recruited from 26 general practice clinics in Buckinghamshire and Oxfordshire in the United Kingdom. All participants received 8 weeks of 15-mg NRT transdermal patch. Confirmation of abstinence was defined as an exhaled CO of less than 10 parts per million (ppm), or salivary cotinine concentration of less than 15 ng/ml. Results Cox regression analysis indicated a significant effect of the COMT genotype on relapse into smoking (P=0.001), with shorter times to relapse being observed among the AG (Val/Met) and GG (Val/Val) genotype groups. These effects were observed both during active treatment and as soon as active treatment had ended. The effect, however, was greater, once active treatment had ended, in the subgroup of smokers who had abstained up to this point. We did not observe any evidence of a sex difference in the effect of the COMT genotype. These effects did not seem to be mediated by self-reported withdrawal or mood symptoms. Conclusions Our results indicate that the COMT genotype is associated with the likelihood of smoking cessation in smokers treated with the NRT transdermal patch. Future large-scale studies will be required to afford sufficient power to simultaneously investigate the role of multiple genetic variants in treatment responses, and the effects of potential moderating variables on these associations.