OBJECTIVES: The aim of this study was to investigate the role of the chemokine receptor CX3CR1 in headaches and migraine. METHODS: Distribution of 2 polymorphisms of the chemokine receptor CX3CR1 (V249I and T280M) was determined in a population-based sample of 1179 elderly individuals. RESULTS: Heterozygotes for both CX3CR1 polymorphisms had a reduced risk of recurrent headaches, with an odds ratio (OR) of 0.64 (95% confidence interval [CI] = 0.46-0.90) for the I249 allele and 0.55 (95% CI = 0.38-0.81) for the M280 allele. Haplotype analysis showed that carriers of the rarer CX3CR1 I249-M280 haplotype had a reduced risk of recurrent headaches, with an OR of 0.57 (95% CI = 0.41-0.80, P = .001). This association was seen for both nonmigraine headaches (OR = 0.47, 95% CI = 0.28-0.79, P = .004) and migraine (OR = 0.65, 95% CI = 0.43-0.98, P = .041). CONCLUSIONS: These results need to be replicated but suggest that the chemokine receptor CX3CR1 may play a role in recurrent headaches.