Background/Aim: Interleukin-8 (IL-8), a potent chemoattractant for neutrophils, has been implicated in the pathogenesis of Alzheimer’s disease (AD). The ability of individuals to produce high levels of IL-8 is partially determined by the IL-8 –251 T/A polymorphism. Therefore, we investigated the association between this polymorphism and AD in a Chinese population. Additionally, in light of the stimulatory effect of homocysteine on the production of IL-8, we also sought to determine whether the methylenetetrahydrofolate reductase (MTHFR) gene 677 C/T variant, a genetic modifier of the serum homocysteine level, may interact with the IL-8 –251 polymorphism in determining the AD risk. Methods: Genotyping of 198 AD patients and 240 matched controls was performed by PCR-RFLP. Results: The presence of the MTHFR 677 C/T and 677 T/T genotypes conferred a marginally significant increase in the risk for AD (OR = 1.666, 95% CI = 1.022–2.715, and OR = 1.892, 95% CI = 1.124–3.187) and the presence of the IL-8 –251 polymorphism was not associated with AD. However, the OR for AD associated with joint occurrence of the MTHFR 677 T/T and the IL-8 –251 A/A genotypes was 2.512 (95% CI = 1.151–5.483). Conclusion: Our data suggest a critical role for IL-8/MTHFR interactions in the development of AD.