Cigarette smoking behavior is influenced by both personality traits and inherited factors. Previous research showed that neuroticism-a broad personality domain that includes anxiety, depression, impulsiveness and vulnerability-increases the risk of being a smoker, primarily because of difficulty in quitting. Neuroticism has also been associated with the 5-HTTLPR, a functional polymorphism in the promoter for the serotonin transporter gene. We used population and family-based methods to analyze the joint effects of the 5-HTTLPR and neuroticism on smoking behavior in a population of 759 never, current, and former smokers, all members of sib-pairs. Our main finding is that smoking behavior is influenced by an interaction between neuroticism and 5-HTTLPR genotype. Specifically, neuroticism was positively correlated with current smoking and negatively associated with smoking cessation in individuals and siblings with poorly transcribed 5-HTTLPR-S genotypes, but not in those with the more highly expressed 5-HTTLPR-L genotype. Individuals with both a 5-HTTLPR-S genotype and a high level of neuroticism had the greatest difficulty in quitting smoking. These data, if replicated, suggest that smoking behavior is more strongly influenced by the combination of the serotonin transporter gene and neuroticism than by either factor alone, and that personality scores and 5-HTTLPR genotype may predict the clinical efficacy of certain smoking cessation drugs.