Mutations in the gene CACNA1A have been known to cause familial hemiplegic migraine (FHM); it has been suggested, based on indirect genetic studies, that this gene may also be involved in common forms of migraine. To obtain data from direct gene analysis to test this hypothesis, we investigated 143 patients with common migraine, irrespective of their family history, for the presence of mutations known to result in the FHM phenotype; the mutations V714A, R192Q, R583Q, T666M, V1457L, and I1811L were absent in our patient sample. Furthermore, exons 4, 16, 17, and 36 were completely screened by single-strand conformation polymorphism (SSCP), and no other, hitherto unknown, mutations were detected. Bearing in mind that, in particular, the T666M mutation contributes to a large proportion of FHM linked to chromosome 19, we conclude that common migraine is distinct from FHM in its molecular basis and, therefore, most likely also in its pathophysiology. The possibility, however, of the existence of allelic disorders, with mutations located in other regions of the CACNA1A gene, cannot be ruled out. Molecular testing, therefore, is at present not a feasible option for the diagnosis and classification of migraine.