The relationship of the dopamine D4 receptor gene (DRD4) to the behavioral trait of novelty seeking has not been uniformly consistent. A methodological shortcoming in previous studies may relate to the way different DRD4 variants were categorized. Because of evolutionary and functional (e.g., diminished potency to reduce cAMP) similarities between the 2- and 7-repeat (2R, 7R) alleles of the DRD4, we suggest grouping of these two alleles together may facilitate detection of biologically meaningful and reproducible association findings with behavioral traits. We measured novelty seeking with the Tridimensional Personality Questionnaire (TPQ) in a community sample of Caucasian, Korean, and Filipino subjects (N = 171) who were subsequently characterized for the DRD4 variable number of tandem repeats (VNTR). In the Korean sample, those with a 2R and/or 7R allele scored significantly higher on novelty seeking scale (P < 0.05). By contrast, grouping the VNTR alleles by size (2, 3, 4 vs. 5, 6, 7), as has been done in similar studies of Asian subjects, was not significant. Using the extreme discordant phenotype (EDP) strategy in the pooled sample and selecting the individuals within the upper and lower decile, we observed a trend for association with higher novelty seeking in individuals who carry the 2R and/or 7R alleles (P = 0.06). We also confirmed that the 2R allele in the Korean and Filipino subjects was the result of a one-step recombination event between the 4R and 7R alleles. This study suggests that genetic association analyses can benefit by consideration of the shared functional and evolutionary attributes of the DRD4 2R and 7R alleles. © 2007 Wiley-Liss, Inc.