Although it is well-established that genetic variation is important in causing individual differences in many human personality traits or based on family, twin, and adoption studies, the first reports that specific genetic polymorphisms might influence a normal dimension of personality were only recently published. Specifically, two studies have described significant associations between a dopamine D4 receptor (D4DR) exon III 48-base pair (bp) insertion/deletion polymorphism and the personality traits of novelty-seeking and positive emotional experience [Benjamin et al. (1996): Nat Genet 12: 81-84; Ebstein et al. (1996): Nat Genet 12:78-80]. The present study was undertaken to attempt to replicate these important and heuristic initial findings. Personality questionnaires measuring novelty-seeking and positive emotional experience were administered to 306 male and female young adult twins (monozygotic 92 pairs, dizygotic 61 pairs) from the general population, 281 of whom were genotyped for D4DR exon I and III polymorphisms. No significant associations were observed between novelty-seeking or positive emotional experience and these D4DR polymorphisms. This failure to replicate the initial reports seems unlikely to represent measurement or genetic differences across studies, although environmental differences may be possible. Adequate statistical power in the present study suggests that these results are unlikely to be statistical "false negatives" and instead may reduce confidence in the generality of the initial positive findings.