||Background: Migraine seems to be caused by a combination of environmental and genetic factors. Clinical and pharmacologic evidence supports the hypothesis that dopaminergic transmission is involved in the pathogenesis of migraine. Objective: The current report concerns a genetic study of test the involvement of genes for dopamine (DA) receptors D2 (DRD2), D3 (DRD3), and D4 (DRD4) in migraine without aura, particularly in a subgroup with enhanced DA sensitivity. Methods: For the first time, a family-based association method-the Transmission Disequilibrium Test (TDT)-was used to examine an isolated population, such as Sardinians. We studied 50 nuclear families of patients affected by migraine without aura. The subgroup of dopaminergic migraineurs was selected based o the presence of both nausea and yawning immediately before or during the pain phase of migraine. Results: No association was detected using the TDT between DRD3, DRD4, and migraine without aura either in the overall sample or in the subgroup. No difference was observed in DRD2 allelic distribution in the overall sample, although the allelic distribution at the DRD2 locus differed significantly in the subgroup of dopaminergic migraineurs (p = 0.004). Allele 1 of the TG dinucleotide intronic noncoding polymorphism of the DRD2 locus was the individual allele that appeared to be in disequilibrium with migraine without aura (p = 0.02). Conclusions: Our data suggest that a genetic approach could be useful in providing molecular support to the hypothesis that hypersensitivity of the dopaminergic system may represent the pathophysiologic basis of migraine, at least in a subgroup of patients.