White matter hyperintensities (WMHs) in migraine could be related to inflammatory and antioxidant events. The aim of this study is to verify whether migraine patients with WMHs carry a genetic pro-inflammatory/pro-oxidative status. To test this hypothesis, we analyzed (; rs2071590T and rs2844482G) and (; rs2234694C) and 2 (; rs4880T) gene polymorphisms (SNPs) in 370 consecutive patients affected by episodic (EM; n = 251) and chronic (CM; n = 119) migraine and in unrelated healthy controls (n = 100). Brain magnetic resonance was available in 183/370 patients. The results obtained show that genotypes and allele frequencies for all tested SNPs did not differ between patients and controls. No association was found between single SNPs or haplotypes and sex, migraine type, cardiovascular risk factors or disorders. Conversely, the rs2071590T (OR = 2.2) and the rs2234694C (OR = 4.9) alleles were both associated with WMHs. A four-loci haplotype ( haplotype: rs2071590T/rs2844482G/rs2234694C/rs4880T) was significantly more frequent in migraineurs with WMHs (7 of 38) compared to those without WMHs (4 of 134; OR = 8.7). We may, therefore, conclude by suggesting that that an imbalance between pro-inflammatory/pro-oxidative and antioxidant events in genetically predisposed individuals may influence the development of WMHs.