5-Hydroxytryptamine (5HT), commonly known as serotonin, which predominantly serves as an inhibitory neurotransmitter in the brain, has long been implicated in migraine pathophysiology. This study tested an MspI polymorphism in the human 5HT2A receptor gene (HTR2A) and a closely linked microsatellite marker (D13S126), for linkage and association with common migraine. In the association analyses, no significant differences were found between the migraine and control populations for both the MspI polymorphism and the D13S126 microsatellite marker. The linkage studies involving three families comprising 36 affected members were analysed using both parametric (FASTLINK) and non-parametric (MFLINK and APM) techniques. Significant close linkage was indicated between the MspI polymorphism and the D13S126 microsatellite marker at a recombination fraction (theta) of zero (lod score = 7.15). Linkage results for the MspI polymorphism were not very informative in the three families, producing maximum and minimum lod scores of only 0.35 and -0.39 at recombination fractions (theta) of 0.2 and 0.00, respectively. However, linkage analysis between the D13S126 marker and migraine indicated significant non-linkage (lod < -2) up to a recombination fraction (theta) of 0.028. Results from this study exclude the HTR2A gene, which has been localized to chromosome 13q14-q21, for involvement with common migraine.