In light of the lack of research in polymorphism–polymorphism interactions in the Japanese population, we here investigated whether the combined polymorphic variants of SLC6A3 and ANKK1/DRD2, in the context of CYP2A6*4 genotypes, are associated with smoking-related phenotypes in a Japanese population, focussing on smoking cessation and nicotine dependence. This evidence concerns the gene ANKK1 and nicotine dependence.