Objective The Met/Val functional polymorphism of the gene-encoding catechol-O-methyltransferase (COMT) is one of the most widely tested variants for association with different phenotypes of addictive behavior, but replication has been inconsistent for smoking status. We investigated the relationship of this COMT single nucleotide polymorphism with smoking cessation in elderly persons in retrospective and prospective analyses. Methods The study is embedded in the population-based Rotterdam Study cohort and included 5115 persons aged 55 years and more. In the retrospective analyses using logistic regression, current smokers who had smoked 10 or more cigarettes daily for 10 or more years were compared with former smokers. In the prospective analyses, we followed 1195 current smokers up to 12 years and used Cox proportional hazard model to detect the effect of the COMT single nucleotide polymorphism on self-reported incidence of smoking cessation. Results The Val/Val genotype of COMT had a consistent association with smoking cessation as compared with the Met/Met+Met/Val genotypes in retrospective [odds ratio=0.79, 95% confidence interval (CI): 0.66-0.96, P=0.02] and prospective analyses (hazard ratio=0.80, 95% CI: 0.63-1.01, P=0.06). In the pooled analyses of prevalent and incident cessation cases that we compared with persisting smokers, the odds ratio was 0.70 (95% CI: 0.55-0.88, P=0.003). No sex difference and no effect of the COMT polymorphism on smoking initiation were observed. Conclusion Our results suggest that COMT Met/Val polymorphism is strongly associated with smoking cessation. The Met allele is the risk allele that decreases the likelihood of smoking cessation in men and women. Pharmacogenetics and Genomics 19:45-51 (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.