The nicotine metabolism of CYP2A6 (CYP2A6*1A,*1B, and *1C), and the cholecystokinin (CCK; which modulates the release of dopamine) and CCK-A receptor gene and personality traits for NEO-FFI, was investigated for the mechanism for elucidation of the smoking behavior in Japanese populations. The frequency of the CYP2A6*4C allele, which is a whole deleted allele of the human CYP2A6 gene, was higher, whereas that of CYP2A6*1A/*1B heterozygotes with higher nicotine metabolism activity was lower in nonsmokers than in smokers. There was also a significant difference between the current smoking and nonsmoking groups in the allele frequency of the CCK -45C/T polymorphism. It was also shown that the Openness (O) factor for smokers was significantly higher than that of nonsmokers; however, there were no significant differences in the Neuroticism (N), Extraversion (E), Agreeable (A), and Conscientiousness (C) scores among smokers than nonsmokers. It was suggested that the CYP2A6*4C allele may prevent the carrier from smoking, and being a CYP2A6*1A/*1B heterozygote and the CCK T allele may be risk factors for developing smoking behavior. Also, it is possible that persons with a low score in Openness may be refraining from smoking because they have a general negative impression toward smoking.