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 rheumatoid arthritis (RA) in populations with different ethnicities. MEDLINE and EMBASE databases and manual search were used to identify articles in which TNF-α polymorphism was determined in RA patients and controls. A meta-analysis was conducted on the associations between the TNF-α -308 A/G polymorphism and RA by using (1) allelic contrast and (2) dominant models. A total of 19 studies involving 2,584 RA patients and 3,254 controls were considered. The meta-analysis showed no association between the TNF-α -308 A allele and RA when all the subjects were considered [odds ratio (OR) = 1.129, 95 % CI 0.843-1.513, P = 0.416]. After stratification by ethnicity, the meta-analysis indicated that the A allele was significantly associated with RA in Latin Americans (OR = 1.620, 95 % CI 1.234-2.111, P = 3.6 × 10(-5)), but not in the European, Arab, or Asian populations. The meta-analysis of the AA/AG genotype showed the same pattern of results as with the A allele. No association was noted between the AA/AG genotype and RA when all the subjects were considered (OR = 1.114, 95 % CI 0.812-1.529, P = 0.503), but stratification by ethnicity revealed that the AA/AG genotype was significantly associated with RA in Latin Americans (OR = 1.650, 95 % CI 1.234-2.104, P = 0.001). This meta-analysis showed that the TNF-α -308 A/G polymorphism may represent a significant risk factor for RA in Latin Americans but not in the European, Arab, or Asian populations.