The aim of this study was to determine whether the tumor necrosis factor-α (TNF-α) promoter -308 A/G polymorphism is associated with susceptibility to Alzheimer's disease (AD) in multi-ethnic populations. MEDLINE and EMBASE databases and manual literature search were used to identify published articles in which TNF-α polymorphism was determined in AD patients and control subjects. Meta-analysis was conducted on the association between the TNF-α -308 A/G polymorphism and AD using allele contrast and the recessive, dominant, and additive models. A total of 16 studies involving 3,826 AD patients and 4,327 control subjects were examined. The meta-analysis showed no association between the TNF-α -308 A allele and AD when all the subjects were considered [odds ratio (OR) = 1.275, 95 % CI 0.966-1.685, p = 0.087]. After stratification by ethnicity, the meta-analysis indicated that the A allele is significantly associated with AD in East Asian (OR = 1.743, 95 % CI 1.256-2.418, p = 0.001), but not in the European (OR = 0.963, 95 % CI 0.822-1.128, p = 0.637) or Middle Eastern populations (OR = 3.921, 95 % CI 0.411-37.42, p = 0.235). Meta-analysis under dominant, recessive, and additive models also showed a similar pattern of results as with the A allele. This meta-analysis shows that the TNF-α -308 A/G polymorphism may represent a significant risk factor for AD in East Asians but not in the European or Middle Eastern populations.