To assess the possibility of an association between TNF gene polymorphisms and migraine without aura, a case-control study was performed in a Sardinian sample. Migraine without aura is a complex genetic disease in which susceptibility and environmental factors contribute towards its development. Several studies suggest that tumour necrosis factors (TNF) (TNF-alpha and lymphotoxin-alpha or TNF-ss) may be involved in the pathophysiology of migraine. The TNF-alpha and TNF-ss genes are located on chromosome 6p21.3 in the human leukocyte antigene (HLA) class III region. We evaluated 299 patients affected by migraine without aura (I.H.S. criteria 2004) and 278 migraine-free controls. The polymorphisms G308A of the TNF- alpha gene, and G252A of TNF-beta gene were determined by NcoI restriction fragment length polymorphism analysis. We found a statistically significant difference in allele (p = 0.018; OR = 1.46 95 % CI: 1.066 to 2.023) and genotype (trend chi2 = 5.46, df = 1, p = 0.019) frequencies of TNF-beta gene, between cases and controls. Allele and genotype frequencies of TNF-alpha polymorphism did not differ significantly between the two groups. These data suggest that subjects with the TNFB2 allele have a low risk of developing migraine without aura and/or that the polymorphism of the TNF-beta gene is in linkage disequilibrium with other migraine responsible genes in the HLA region.