The 32-kDa dopamine- and cAMP-regulated phosphoprotein (DARPP-32) is a key signaling factor in several neurotransmitter pathways (including dopamine and serotonin) that impact personality traits. Therefore, different DARPP-32 alleles may influence the biological determination of distinct personality types. We established an association between the DARPP-32 gene polymorphisms (rs12601930C/T, rs879606A/G, and rs3764352A/G) and personality traits as measured by the Tridimensional Personality Questionnaire in 502 healthy Chinese-Han subjects. Of the three polymorphic sites examined, rs12601930C/T was associated with novelty seeking (χ² = 13.06, P = 0.001), while both rs879606A/G and rs3764352A/G were associated with harm avoidance (rs879606: χ² = 7.74, P = 0.021; rs3764352: χ² = 8.53, P = 0.014). There was no significant association between reward dependence scores and DARPP-32 gene polymorphisms. Our results suggest that polymorphisms in the DARPP-32 gene are involved in the biological mechanisms that confer the traits of novelty seeking and harm avoidance.