The functional implications of the dopamine D4 receptor gene (DRD4) exon III polymorphism and its role in the modulation of temperament and in the pathophysiology of psychiatric disorders are still a matter of debate. Based on evidence from animal studies, we hypothesised that this polymorphism is involved in the modulation of the cortical response to novelty as reflected by the auditory evoked novelty P3 event-related potential. In a sample of 46 healthy volunteers, we observed an interactive effect of DRD4 exon III genotype and the eye-blink rate, a measure of central dopaminergic activity, on the novelty P3. These findings suggest that the DRD4 exon III polymorphism influences the processing of novelty and that this influence depends on tonic dopaminergic activity.