A Spanish sample consisting of 68 Caucasian pathological gambling patients (47 males and 21 females) and 68 unaffected controls were screened by the molecular analysis of a functional DNA polymorphism in the locus for the D4 dopamine receptor gene. Our results are consistent with the existence of a significant association between genetic variants at a DRD4 gene polymorphism and pathological gambling (chi 2 = 11.82; P = 0.037). This association seems to be sex-influenced, since there was no significant association when only males were considered (chi 2 = 9.45; P = 0.09), but there was a more significant association if we only considered female subjects (chi 2 = 8.73; P = 0.033). Individuals with the longest allele (D7) were the most frequent in affected females (chi 2 = 4.50; P = 0.033). This work provides a new evidence of the implication of the dopaminergic reward pathways, now through the involvement of DRD4, in the aetiology of this impulsive disorder.