Novelty Seeking (NS) is a human personality trait in which impulsive, exploratory, and thrill-seeking behaviors are displayed. Dopaminergic genes have been prime candidates in the search for the genetic factors underlying NS because of the central role that dopamine plays in the brain's reward system. We have investigated whether there is an association between a polymorphic 120 base pairs (bp) repeat that is located in the 5′-untranslated region of the dopamine D4 receptor gene (DRD4) and NS. We genotyped four separate groups from psychiatric clinical studies for the repeat polymorphism. There were significant associations with NS in the groups of bipolar (P = 0.01) and alcoholic (P = 0.006) families containing 267 and 172 subjects, respectively. Subjects who were homozygous for the single-copy allele (SS genotype) had higher mean NS scores. This trend was also observed in the two other studies that contained unrelated subjects diagnosed with depression (N = 143 and N = 148) but the associations between DRD4 duplication genotype and NS were not significant in these groups. In the data combined from all four clinical groups those genotyped as SS had higher mean scores for all four NS subscales with significant associations for impulsivity (P = 0.0006), extravagance (P = 0.04), disorderliness (P = 0.02), and total NS (P = 0.0003). However, given the low frequency of the single-copy allele, this polymorphism would account for only a small proportion of the variance of NS in the population. © 2003 Wiley-Liss, Inc.